ChemPartner Co.

Shanghai, China

ChemPartner Co.

Shanghai, China

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SPII facilitates and accelerates drug discovery by offering funding, incubator space, and other essential support to its collaborators. The partnership with TSRI marks a major new initiative for SPII to enable its mission to support therapeutic research at the earliest stages with the ultimate goal of getting innovative new treatments to patients. Under the terms of the collaboration, institute scientists will put forth translational research projects to a joint committee comprising drug discovery experts across TSRI, Calibr, and SPII.  In turn, SPII will contribute cash and in-kind services totaling up to $15 million over an initial term of three years. TSRI and Calibr will retain control over assets resulting from the collaboration, with SPII receiving a significant share of future value. "We are delighted to partner with an experienced group that has complementary infrastructure and resources," said Peter G. Schultz, Ph.D., President of TSRI and Calibr. "This new initiative allows us to further accelerate our mission of creating new medicines for unmet needs in a nimble partnership structure designed to mature the programs before out-licensing, creating significant value for patients as well as for the institute." "Biomedical R&D is one of the most challenging areas of science across all disciplines and industries. Strategic partnerships often drive success in making the impossible possible. That is exactly what we plan to do in this alliance with TSRI and Calibr," stated Walter H. Moos, Ph.D., CEO of SPII. "Unlocking the potential of top investigators at TSRI and Calibr to advance novel therapies and ultimately to save and improve lives is our joint goal." The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists - including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine - work toward their next discoveries. The institute's graduate program, which awards doctoral degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www.scripps.edu/. ShangPharma Innovation Inc., founded in the US in 2016, facilitates and accelerates drug discovery, focusing on both therapeutics and technology platforms, and offers funding, incubator space, and other support to its ecosystem of collaborators, partners, and tenants. This includes sponsoring proof-of-concept research at academic and major medical centers, research institutes, and seed-stage start-ups, leading to industry collaborations and venture capital financing. ShangPharma Innovation and ChemPartner are affiliates and preferred partners. Services will be provided predominantly or solely by ChemPartner at their standard commercial rates. Shanghai ChemPartner Co. Ltd., along with its subsidiary entities, is a leading research organization providing high-quality and cost-effective contract research services for the biopharmaceutical industry. ChemPartner offers integrated services across the drug discovery and development process to pharmaceutical and biotechnology companies worldwide. ChemPartner's dedication to life science is seen through its broad range of services, from discovery biologics, discovery chemistry, discovery biology, and preclinical development through pharmaceutical development and manufacturing services for small molecules and biologics. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/the-scripps-research-institute-and-shangpharma-innovation-announce-translational-research-collaboration-300470942.html


News Article | June 19, 2017
Site: www.prnewswire.com

ShangPharma, a leading life science partnering organization providing high-quality and cost-effective drug development and discovery services, technology, and investment for the pharmaceutical and biotechnology industry, announced today the intent to join with Quantum Hi-Tech China Biological Co. Ltd. Quantum, in a press release earlier this week, announced their intent to purchase Shanghai ChemPartner, ShangPharma's Contract Research and Contract Manufacturing Organizations (CRO/CMO). This type of merger approach was addressed in a press release by ShangPharma in March and is part of the company's plans to leverage the capital market in China that has been adopted by several biopharmaceutical industry leaders. "Our team is excited to take another step forward with our plans to list on the Chinese stock exchange.  We believe Quantum is the right partner to help Shanghai ChemPartner achieve its vision and goals as a public company.  A merger would enable both companies to create more value for shareholders. There is no area of business overlap between the two organizations, and Shanghai ChemPartner will be preserved as a stand-alone CRO/CMO business," stated Michael Hui, Chairman and CEO of ShangPharma. This news follows the corporate restructuring of Shanghai ChemPartner earlier this year. Should the Chinese Regulatory Securities Commission approve the merger, the expected timeline for deal closure would be at the end of 2017. "Shanghai ChemPartner is pleased to have successfully completed a strategic restructuring process, resulting in no functional change to our CRO and CMO businesses.  After merger approval, our operational plan is to maintain organizational integrity and remain an autonomous corporate division with our leadership intact.  Shanghai ChemPartner's name will remain the same, and we will continue to provide uninterrupted services to our clients with the existing staff, located at the current facilities, under the same leadership.  We will continue to invest in our CRO/CMO businesses and increase the breadth and depth of our service offerings to meet the emerging needs of our clients," said Livia Legg, Chief Commercial Officer of Shanghai ChemPartner and General Manager of ChemPartner Corporation (US) and ChemPartner EU. Shanghai ChemPartner, which includes ChemPartner, China Gateway Pharmaceutical Development, China Gateway Biologics, and ChemExplorer, offers a broad range of drug discovery and development capabilities including discovery biologics, discovery chemistry, discovery biology, DMPK, CMC, and biologics manufacturing. Shanghai ChemPartner serves a diverse global client base and has laboratories, business offices, and representatives in the US, Europe, China, and Japan. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/shangpharma-announces-second-milestone-in-move-to-enter-chinese-capital-market-300475445.html


- World-class research institute and new innovation center partner to accelerate early translational research - LA JOLLA, Calif., June 8, 2017 /PRNewswire/ -- The Scripps Research Institute (TSRI) and ShangPharma Innovation, Inc. (SPII) today announced a strategic collaboration to accelerate the development of innovative drug candidates through scientific collaboration, a services relationship with Shanghai ChemPartner Co. Ltd. (ChemPartner), and sponsored research at TSRI and its drug discovery affiliate, California Institute for Biomedical Research (Calibr). The parties aim to leverage the drug discovery pipeline, expertise, and momentum emerging from the TSRI and Calibr affiliation announced late last year. SPII facilitates and accelerates drug discovery by offering funding, incubator space, and other essential support to its collaborators. The partnership with TSRI marks a major new initiative for SPII to enable its mission to support therapeutic research at the earliest stages with the ultimate goal of getting innovative new treatments to patients. Under the terms of the collaboration, institute scientists will put forth translational research projects to a joint committee comprising drug discovery experts across TSRI, Calibr, and SPII.  In turn, SPII will contribute cash and in-kind services totaling up to $15 million over an initial term of three years. TSRI and Calibr will retain control over assets resulting from the collaboration, with SPII receiving a significant share of future value. "We are delighted to partner with an experienced group that has complementary infrastructure and resources," said Peter G. Schultz, Ph.D., President of TSRI and Calibr. "This new initiative allows us to further accelerate our mission of creating new medicines for unmet needs in a nimble partnership structure designed to mature the programs before out-licensing, creating significant value for patients as well as for the institute." "Biomedical R&D is one of the most challenging areas of science across all disciplines and industries. Strategic partnerships often drive success in making the impossible possible. That is exactly what we plan to do in this alliance with TSRI and Calibr," stated Walter H. Moos, Ph.D., CEO of SPII. "Unlocking the potential of top investigators at TSRI and Calibr to advance novel therapies and ultimately to save and improve lives is our joint goal." The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists - including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine - work toward their next discoveries. The institute's graduate program, which awards doctoral degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www.scripps.edu/. ShangPharma Innovation Inc., founded in the US in 2016, facilitates and accelerates drug discovery, focusing on both therapeutics and technology platforms, and offers funding, incubator space, and other support to its ecosystem of collaborators, partners, and tenants. This includes sponsoring proof-of-concept research at academic and major medical centers, research institutes, and seed-stage start-ups, leading to industry collaborations and venture capital financing. ShangPharma Innovation and ChemPartner are affiliates and preferred partners. Services will be provided predominantly or solely by ChemPartner at their standard commercial rates. Shanghai ChemPartner Co. Ltd., along with its subsidiary entities, is a leading research organization providing high-quality and cost-effective contract research services for the biopharmaceutical industry. ChemPartner offers integrated services across the drug discovery and development process to pharmaceutical and biotechnology companies worldwide. ChemPartner's dedication to life science is seen through its broad range of services, from discovery biologics, discovery chemistry, discovery biology, and preclinical development through pharmaceutical development and manufacturing services for small molecules and biologics. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/the-scripps-research-institute-and-shangpharma-innovation-announce-translational-research-collaboration-300470942.html


News Article | June 19, 2017
Site: en.prnasia.com

ShangPharma, a leading life science partnering organization providing high-quality and cost-effective drug development and discovery services, technology, and investment for the pharmaceutical and biotechnology industry, announced today the intent to join with Quantum Hi-Tech China Biological Co. Ltd. Quantum, in a press release earlier this week, announced their intent to purchase Shanghai ChemPartner, ShangPharma's Contract Research and Contract Manufacturing Organizations (CRO/CMO). This type of merger approach was addressed in a press release by ShangPharma in March and is part of the company's plans to leverage the capital market in China that has been adopted by several biopharmaceutical industry leaders. "Our team is excited to take another step forward with our plans to list on the Chinese stock exchange.  We believe Quantum is the right partner to help Shanghai ChemPartner achieve its vision and goals as a public company.  A merger would enable both companies to create more value for shareholders. There is no area of business overlap between the two organizations, and Shanghai ChemPartner will be preserved as a stand-alone CRO/CMO business," stated Michael Hui, Chairman and CEO of ShangPharma. This news follows the corporate restructuring of Shanghai ChemPartner earlier this year. Should the Chinese Regulatory Securities Commission approve the merger, the expected timeline for deal closure would be at the end of 2017. "Shanghai ChemPartner is pleased to have successfully completed a strategic restructuring process, resulting in no functional change to our CRO and CMO businesses.  After merger approval, our operational plan is to maintain organizational integrity and remain an autonomous corporate division with our leadership intact.  Shanghai ChemPartner's name will remain the same, and we will continue to provide uninterrupted services to our clients with the existing staff, located at the current facilities, under the same leadership.  We will continue to invest in our CRO/CMO businesses and increase the breadth and depth of our service offerings to meet the emerging needs of our clients," said Livia Legg, Chief Commercial Officer of Shanghai ChemPartner and General Manager of ChemPartner Corporation (US) and ChemPartner EU. Shanghai ChemPartner, which includes ChemPartner, China Gateway Pharmaceutical Development, China Gateway Biologics, and ChemExplorer, offers a broad range of drug discovery and development capabilities including discovery biologics, discovery chemistry, discovery biology, DMPK, CMC, and biologics manufacturing. Shanghai ChemPartner serves a diverse global client base and has laboratories, business offices, and representatives in the US, Europe, China, and Japan. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/shangpharma-announces-second-milestone-in-move-to-enter-chinese-capital-market-300475445.html


SHANGHAI, July 12, 2017 /PRNewswire/ -- Shanghai ChemPartner today announced the appointment of Lilly Xu, Ph.D. as Vice President and the Head of DMPK and Exploratory Toxicology at the company headquarters in Shanghai, China. Dr. Xu has more than 20 years of experience in the area of drug metabolism, pharmacokinetics and toxicology. She was one of the pioneers in developing cultured human hepatocytes as a tool to study metabolism of xenobiotics and induction of P450 isozymes. Prior to joining ChemPartner, Dr. Xu was the Head of the Center of Predictive ADMET at Sanofi/Icagen. She received her Ph.D. in Cell and Molecular Biology from Saint Louis University. Since the DMPK and Exploratory Toxicology department's inception in 2006, it has been one of the most rapidly growing business units in the company. This growth is a testament to the high-quality performance and experienced leadership by the scientific team. "DMPK is important to Chempartner and our biopharmaceutical clients with respect to drug discovery and development to meet unmet medical needs. We needed an experienced leader to maintain the quality of service that keep our clients satisfied and coming back. Dr. Xu's expertise, knowledge, and dedication make her a great fit for the team," said Dr. Wei Tang, President of ChemPartner. Dr. Tang previously served as Senior Vice President, Biology, Biologics, and DMPK and hired Dr. Xu  to lead the talented team. "ChemPartner's DMPK Exploratory Toxicology integrated service, working in unison with our Chemistry, Biologics, and Biology departments, is the best model for helping our clients to deliver their hits, leads, and candidates in a fast and high quality manner. Our goal at ChemPartner has always been to deliver high quality data to our clients and provide scientific interpretation of the data, thereby helping to solve problems through our expertise in DMPK and toxicology," said Dr. Xu. ChemPartner's DMPK and Exploratory Toxicology department consists of bioanalytical (small and large molecules, discovery, and regulated), in vitro ADME, in vivo pharmacokinetics, and toxicology (non-GLP and partnered GLP) groups. Working closely with Chemistry, Biology/Pharmacology, and Biologics, the department supports translational medicine with experience in formulation development, in vitro and in vivo PK extrapolation, PK/PD correlation, and biomarker analysis including metabolomics. Shanghai ChemPartner is a full-service life science CRO with over 15 years of pharmaceutical research experience. With a team of over 2000 experienced scientists, hundreds of western-trained pharmaceutical industry leaders, and experienced pharmaceutical executive leadership at the helm, ChemPartner is aligned and dedicated to technically and strategically accomplishing the research initiatives of pharma and biotech companies worldwide.


SAN FRANCISCO and SOUTH SAN FRANCISCO, Calif., July 13, 2017 /PRNewswire/ -- In a new collaboration, ShangPharma Innovation, Inc. (SPII) is providing funding and other support to scientists at UC San Francisco (UCSF) to accelerate the development of promising life science inventions. The partnership helps advance a major new initiative at UCSF to bridge academic research with industrial development. Part of this effort, which SPII will support, involves backing preclinical research to validate drug targets and to develop programs to discover new drugs. Drugs that UCSF and SPII determine to be promising in preclinical studies can then be readied for clinical trials to demonstrate safety and efficacy in patients. The collaboration agreement anticipates that SPII will provide several years of funding to carry out R&D in UCSF laboratories. SPII also will commit to spend additional amounts each year during the term of the collaboration to purchase Contract Research Organization (CRO) services in support of the projects being conducted by SPII and UCSF. CRO services will be provided by Shanghai ChemPartner Co. Ltd. (ChemPartner). SPII and UCSF will share in future value created through this innovative partnership. "When the proper bridges to fundamental research are built, important new medicines reach the marketplace, saving and improving lives around the world," said Walter H. Moos, PhD, CEO of SPII and adjunct professor of pharmaceutical chemistry at UCSF. "We have only just begun to scratch the surface of what's possible when academia and early-stage investors come together to advance novel discoveries. We look forward to enabling biomedical innovation across all borders and disciplines." Cathy Tralau-Stewart PhD, interim director of UCSF's Catalyst Program and adjunct associate professor of bioengineering and therapeutics at UCSF, said, "The translation of early research into novel therapeutics for patients requires a wide range of expertise and capabilities. This collaboration will give UCSF access to the broad range of expertise and services required and will enable the translation of more UCSF discoveries to product opportunities with real potential benefit for patients. This is an important collaboration and we look forward to working closely with the ShangPharma and ChemPartner teams." ShangPharma Innovation, Inc., founded in the US in 2016, facilitates and accelerates drug discovery, focusing on both therapeutics and technology platforms, and offers funding, incubator space, and other support to its ecosystem of collaborators, partners, and tenants. This includes sponsoring proof-of-concept research at major academic and medical centers, research institutes, and seed-stage start-ups, leading to industry collaborations and venture capital financing. ShangPharma Innovation and ChemPartner are affiliates and preferred partners. Services will be provided predominantly or solely by ChemPartner at their standard commercial rates. For more information, see http://www.shangpharmainnovation.com. UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit www.ucsf.edu/news. The Catalyst program, which is part of UCSF's Innovation Ventures, accelerates translation of research into products with clinical impact through funding, mentorship, and identification of resources. Catalyst aims to foster academic and industry collaborations as well as enhance education in early translational research and entrepreneurship. See http://ctsi.ucsf.edu/catalyst. Shanghai ChemPartner Co. Ltd., along with its subsidiary entities, is a leading research organization providing high-quality and cost-effective contract research services for the biopharmaceutical industry. ChemPartner offers integrated services across the drug discovery and development process to pharmaceutical and biotechnology companies worldwide. ChemPartner's dedication to life science is seen through its broad range of services, from discovery biologics, discovery chemistry, discovery biology, and preclinical development through pharmaceutical development and manufacturing services for small molecules and biologics. For more information, see http://www.chempartner.com.


The partnership helps advance a major new initiative at UCSF to bridge academic research with industrial development. Part of this effort, which SPII will support, involves backing preclinical research to validate drug targets and to develop programs to discover new drugs. Drugs that UCSF and SPII determine to be promising in preclinical studies can then be readied for clinical trials to demonstrate safety and efficacy in patients. The collaboration agreement anticipates that SPII will provide several years of funding to carry out R&D in UCSF laboratories. SPII also will commit to spend additional amounts each year during the term of the collaboration to purchase Contract Research Organization (CRO) services in support of the projects being conducted by SPII and UCSF. CRO services will be provided by Shanghai ChemPartner Co. Ltd. (ChemPartner). SPII and UCSF will share in future value created through this innovative partnership. "When the proper bridges to fundamental research are built, important new medicines reach the marketplace, saving and improving lives around the world," said Walter H. Moos, PhD, CEO of SPII and adjunct professor of pharmaceutical chemistry at UCSF. "We have only just begun to scratch the surface of what's possible when academia and early-stage investors come together to advance novel discoveries. We look forward to enabling biomedical innovation across all borders and disciplines." Cathy Tralau-Stewart PhD, interim director of UCSF's Catalyst Program and adjunct associate professor of bioengineering and therapeutics at UCSF, said, "The translation of early research into novel therapeutics for patients requires a wide range of expertise and capabilities. This collaboration will give UCSF access to the broad range of expertise and services required and will enable the translation of more UCSF discoveries to product opportunities with real potential benefit for patients. This is an important collaboration and we look forward to working closely with the ShangPharma and ChemPartner teams." ShangPharma Innovation, Inc., founded in the US in 2016, facilitates and accelerates drug discovery, focusing on both therapeutics and technology platforms, and offers funding, incubator space, and other support to its ecosystem of collaborators, partners, and tenants. This includes sponsoring proof-of-concept research at major academic and medical centers, research institutes, and seed-stage start-ups, leading to industry collaborations and venture capital financing. ShangPharma Innovation and ChemPartner are affiliates and preferred partners. Services will be provided predominantly or solely by ChemPartner at their standard commercial rates. For more information, see http://www.shangpharmainnovation.com. UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit www.ucsf.edu/news. The Catalyst program, which is part of UCSF's Innovation Ventures, accelerates translation of research into products with clinical impact through funding, mentorship, and identification of resources. Catalyst aims to foster academic and industry collaborations as well as enhance education in early translational research and entrepreneurship. See http://ctsi.ucsf.edu/catalyst. Shanghai ChemPartner Co. Ltd., along with its subsidiary entities, is a leading research organization providing high-quality and cost-effective contract research services for the biopharmaceutical industry. ChemPartner offers integrated services across the drug discovery and development process to pharmaceutical and biotechnology companies worldwide. ChemPartner's dedication to life science is seen through its broad range of services, from discovery biologics, discovery chemistry, discovery biology, and preclinical development through pharmaceutical development and manufacturing services for small molecules and biologics. For more information, see http://www.chempartner.com.


News Article | July 24, 2017
Site: www.prnewswire.com

LONDON, July 24, 2017 /PRNewswire/ -- INTRODUCTION The early stages of research related to drug discovery, including the identification of a relevant target and a viable lead compound, play a crucial role in the overall success of a drug in preclinical and / or clinical studies. The process of drug discovery is extremely demanding, both in terms of capital expenses and time. Moreover, there is always a high risk of failure associated with R&D programs and, given the increasing regulatory stringency, the approval of new drugs has become significantly complex as well. Over the years, outsourcing has emerged as a popular trend in the pharmaceutical and biotechnology industry, and has demonstrated the potential to effectively cater to the growing demands associated with drug discovery as well. Contract Research Organizations (CROs), with dedicated teams of experts and innovative solutions across the various stages of the drug discovery and development process, are now located in all major global markets. Employing the services of these CROs offers a number of benefits to drug developers, including access to better technologies, latest R&D tools, cost and time savings and the potential to minimize risks associated with the drug discovery process. Download the full report: https://www.reportbuyer.com/product/5015345/ Specifically, the oncology market, with an estimated global prevalence of 32 million, imposes a heavy burden on the healthcare system. There exists a significantly high unmet need for novel therapeutic options in this domain, translating into a growing demand for drug discovery initiatives. Therefore, CROs have now emerged as important stakeholders in the oncology market. The increasing trend towards outsourcing has triggered the establishment of several strategic collaborations between drug / therapy developers and CROs. In fact, several CROs have acquired other small / mid-sized CROs or collaborated with them for upgrading their own drug discovery capabilities in an effort to provide integrated services to its clients. Opportunities arising from the growth of personalized medicines, the vast unmet need for therapies for orphan indications, and the adoption of novel technology solutions, such as deep learning solutions, cloud-based technology platforms and 3D cell culture systems, are likely to act as some of the primary drivers of growth within this sector. SCOPE OF THE REPORT The "Oncology Drug Discovery Services Market, 2017-2030" report features an extensive study of the current market landscape and the future potential of CROs providing drug discovery services in oncology. Cancer, one of the leading causes of death worldwide, is an extremely complex disease and medical science is still struggling to figure out the various factors associated with the disease's origin, propagation, spread (metastasis) and relapse. In fact, in 2017, a total of 1.7 million new cancer cases are estimated to be diagnosed in the US alone; during the same time period, close to 0.6 million patients are estimated to die due to cancer. With the increasing complexity of drug discovery and development process, the overall spending on R&D in the pharmaceutical / biotechnology sector has increased over the past few years. According to one particular source, this spending has increased from USD 108 billion in 2006 to USD 145 billion in 2016. Heavy investments are being made towards the discovery of novel approaches for the treatment of various types of cancers. The industry is currently under tremendous pressure not only to meet the expectations of a growing patient population but also to identify ways to address the risks associated with novel drug discovery programs. Over the years, CROs offering drug discovery services have contributed significantly and have now grown to become an integral and indispensable part of the pharmaceutical and biotechnology industry. This study presents an in-depth analysis of a diverse set of companies that offer services across the different steps, such as target identification, target validation, hit generation, hit-to-lead and lead optimization, of the drug discovery process. In addition to other elements, the report features: - A discussion on the current state of the market with respect to key players, along with information on the location of headquarters, drug discovery services provided (target identification, target validation, hit generation, hit-to-lead, lead optimization), depth of service portfolio (discovery / preclinical / clinical / commercial manufacturing) and product type (biologics / small molecules). - Elaborate profiles of established / emerging players. Each profile features a company overview, financial information, drug discovery service portfolio, recent developments and a view on its future outlook and strategy. - An overview of the most active regions in terms of drug discovery services for oncology. The report contains schematic representations of world maps that clearly indicate the location of drug discovery hubs across the world. - A comprehensive benchmark analysis, comparing the existing capabilities of various stakeholders within their respective peer groups, to identify ways to become more competitive in the industry. The analysis is based on key parameters such as the depth of service portfolio, the type of molecules researched and the nature of services offered by different companies. - An analysis of the agreements that have been established in the recent past, covering drug discovery agreements / research collaborations, license agreements, acquisitions, service alliances and joint venture agreements. - A competitive landscape review, featuring a multivariate bubble analysis, based on parameters such as the geographical location, founding year, number of drug discovery services offered and the level of partnering activity in recent years. - A discussion on the potential growth areas such as personalized medicines, orphan drugs and complex biopharmaceuticals, and innovative technologies including deep learning solutions and 3D cell culture systems, that are likely to present opportunities or act as growth drivers during the coming years. In addition, the study features a detailed analysis of the existing market size and the future growth potential of the oncology drug discovery services market for the period 2017-2030. We have provided insights on the likely regional evolution of the market, across North America, Europe, China and the rest of the world. Additionally, we have provided informed estimates of the likely market evolution on the basis of type of product (small molecule, biologics) and key steps of drug discovery (target identification, target validation, hit generation, hit-to-lead and lead optimization). In order to account for the uncertainties associated with some of the key parameters, and to add robustness to our model, we have presented three different forecast scenarios, depicting the conservative, base and optimistic tracks of the market's evolution. The research, analysis and insights presented in this report are backed by a deep understanding of key insights gathered from both secondary and primary research. Actual figures have been sourced and analyzed from publicly available data. For the purpose of this study, we invited over 100 stakeholders to participate in a survey, in order to solicit their opinions on upcoming opportunities, challenges and likely future trends. The opinions and insights presented in this study were also influenced by discussions conducted with experts in this field. RESEARCH METHODOLOGY The data presented in this report has been gathered via secondary and primary research. For all our projects, we conduct interviews with experts in the area to solicit their opinions on emerging trends in the market. This is primarily useful for us to draw out our own opinion on how the market will evolve across different regions and type of biopharmaceuticals. Where possible, the available data has been checked for accuracy from multiple sources of information. The secondary sources of information include: - Annual reports - Investor presentations - SEC filings - Industry databases - News releases from company websites - Government policy documents - Industry analysts' views While the focus has been on forecasting the market till 2030. This opinion is solely based on our knowledge, research and understanding of the relevant market gathered from various secondary and primary sources of information. CHAPTER OUTLINES Chapter 2 presents an executive summary of the insights captured in our research. It offers a high level view on the current state of the oncology drug discovery services market, specific factors impacting its growth and how the opportunity is likely to evolve in the mid-long term. Chapter 3 provides an introduction to the drug discovery approach. It includes details on the time taken for a drug to traverse from the bench to the market, along with a historical account of the evolution of the drug discovery process. It also provides an in-depth explanation of each of the five steps involved in the drug discovery process, including details on associated methods / technologies / approaches. Further, the chapter features a discussion on the key challenges associated with conducting drug discovery research in-house, highlighting the need for contract services providers and the evident shift towards outsourcing drug discovery related operations in oncology. Chapter 4 includes a comprehensive overview and analysis of the current market landscape of the oncology drug discovery services market. It features an analysis of drug discovery service providers on the basis of their geographical location, type of drug discovery service provided, depth of service portfolio (discovery / preclinical development / clinical development / commercial manufacturing) and the nature of product (small molecule / biologic). Chapter 5 provides detailed profiles of some of the oncology drug discovery service providers that offer end-to-end services. Each profile features a brief overview of the company, financial information, insights on drug discovery related services offered by the company, recent developments and a comprehensive future outlook. Chapter 6 provides detailed profiles of some of the oncology drug discovery service providers that offer target based services. Each profile features a brief overview of the company, its financial information, insights on drug discovery related services offered by the company, recent developments and a comprehensive future outlook. Chapter 7 provides detailed profiles of some of the oncology drug discovery service providers that offer lead based services. Each profile features a brief overview of the company, its financial information, insights on drug discovery related services offered by the company, recent developments and a comprehensive future outlook. Chapter 8 provides detailed profiles of some of the oncology drug discovery service providers that specialize in lead optimization. Each profile features presents a brief overview of the company, its financial information, insights on drug discovery related services offered by the company, recent developments and a comprehensive future outlook. Chapter 9 provides a comprehensive market forecast, depicting how the drug discovery services market for oncology is likely to evolve till 2030. We have presented an analysis of the evolving financial opportunity across various regions, such as North America, Europe, China and ROW. Additionally, we have analyzed the market size based on the nature of molecule (biologic, small molecule) and the key steps of drug discovery (target identification, target validation, hit-to-lead, lead identification and lead optimization). It is worth mentioning that our projections are backed by credible data procured from both secondary and primary sources, and a robust forecast approach validated by in-house and external experts. Chapter 10 provides a detailed benchmark analysis of the companies that provide drug discovery services in the oncology domain. The key parameters considered for this analysis include the depth of the service portfolio, the type of the molecule and the number of services offered by each company within a peer group (based on geography and employee base). The analysis allows the companies to compare their existing capabilities within their peer group and identify opportunities to become more competitive in the industry. Chapter 11 features an elaborate discussion and analysis on the collaborations and partnerships that have been recently inked amongst players in this market. We have also discussed the various partnership models that have been implemented, highlighting the most common forms of deals / agreements in this segment of the overall market. In addition to the aforementioned analysis, the chapter offers an illustrative bubble analysis representing the competitive landscape of players involved in the space, based on their experience, number of drug discovery services offered and the level of activity in terms of collaborations established in the field of oncology research. The key objective of this analysis is to establish a region-wise understanding of contract services offerings and key players involved in the oncology drug discovery market globally. Chapter 12 highlights important trends that are likely to impact CROs providing drug discovery services and influence their efforts to strengthen their presence in this competitive market. During our research, we identified a number of interesting trends, including focus on personalized medicines, orphan drugs and complex biopharmaceuticals, innovative applications of deep learning, use of 3 D cell culture systems and other novel technologies, which are being developed to reduce the innate complexities associated with drug discovery and optimize the time spent on the overall process. We believe that these trends are likely to significantly influence the industry's evolution over the coming decade. Chapter 13 presents insights from the survey conducted for this study. The participants, who were primarily Directors / CXO level representatives, helped us develop a deeper understanding on the nature of their services and their associated commercial potential. Chapter 14 summarizes the overall report. It presents a list of key takeaways and offers our independent opinion on the current market scenario and key trends that are likely to determine how the market is likely to evolve in the mid- and long terms. Chapter 15 is a collection of interview transcripts of the discussions held with some of the key players in this industry. Chapters 16 is an appendix, which provides tabulated data and numbers for all the figures in the report. Chapter 17 is an appendix, which contains the list of companies and organizations that have been mentioned in the report. EXAMPLE HIGHLIGHTS 1. During our research, we identified over 115 companies that are actively involved in providing a wide array of oncology drug discovery services; hit-to-lead and lead optimization are amongst the most common services offered by these CROs. 2. Around 25% of the companies offer end-to-end services for drug discovery, starting from target identification till lead optimization. Examples of such one stop shops include (in alphabetical order) Charles River Laboratories, Evotec, GE Healthcare Life Sciences, GenScript, Lonza, PerkinElmer, Syngene, and TCG Lifesciences. 3. The current market is characterized by the presence of several established, as well as emerging CROs. Examples of established players with more than 25 years of overall experience in pharmaceutical sector include AMRI, Aurora Fine Chemicals, Cayman Chemical, ChemDiv, Dalton Pharma Services, DavosPharma, Organix, SRI Biosciences and Syncom. Some of the new players that have recently entered this domain include (in alphabetical order) Abzena, Aurelia Bioscience, Envigo, Enzymlogic, HitGen, INOVOTION, New England Discovery Partners and Tybema BioSolutions. 4. Over 80% of these CROs are located in Europe and North America. It is also worth highlighting that there are several players offering CRO services for oncology drug discovery in certain emerging regions within Asia Pacific, namely India and China. Examples of some of the large-sized CROs based in these locations include (in alphabetical order) Aurigene, GVK Biosciences, Pharmaron, Piramal Pharma Solutions, Sai Life Sciences, ChemPartner and WuXi AppTec. 5. Although the services offered by these companies range from early drug discovery to drug development and commercialization, there are several companies that solely focus on providing drug discovery services. These include (in alphabetical order) Aquila BioMedical, Aris Pharmaceuticals, Attana, Axxam, Beactica, BellBrook Labs, BioDiscovery Group, CanAm Bioresearch, CreaGen Biosciences, Domainex, Evotec, Exiris, Icagen, Organix, Sapient Discovery, Viva Biotech and Zobio. 6. The market has witnessed significant partnering activity in the past three years; several CROs have forged strategic alliances with other services providers in order to expand their drug discovery capabilities. We identified over 70 such collaborations, inked specifically for oncology research. Over 30% of the agreements signed by CROs with other players, including drug / therapy developers or academic players, were focused on co-conducting research for the discovery of either therapeutic targets or lead molecules. Such agreements also involved several big pharma giants, such as (in alphabetical order) AbbVie, AstraZeneca, Daiichi Sankyo, Debiopharm Group, MERCK and Sanofi. Recent examples of acquisitions that we came across include Villapharma's acquisition by Eurofins (January 2017), HD Biosciences' acquisition by Wuxi AppTec (January 2017), Cyprotex's acquisition by Evotec (December 2016) and Blue Stream Laboratories' acquisition by Charles River Laboratories (June 2016). 7. Driven by the rising demand for novel therapeutic targets and drugs, and the growing importance of contract services, we expect the market to continue on its growth trajectory in the foreseen future. We expect the oncology drug discovery services market to grow at an annualized rate of 6.2%, over the period 2017-2030. In terms of geography, majority (more than 70%) of the share is distributed between North America and Europe; other countries, such as China, are likely to grow at a relatively faster rate in the coming decade. Download the full report: https://www.reportbuyer.com/product/5015345/ About Reportbuyer Reportbuyer is a leading industry intelligence solution that provides all market research reports from top publishers http://www.reportbuyer.com For more information: Sarah Smith Research Advisor at Reportbuyer.com Email: query@reportbuyer.com Tel: +44 208 816 85 48 Website: www.reportbuyer.com


News Article | July 6, 2017
Site: globenewswire.com

Dublin, July 06, 2017 (GLOBE NEWSWIRE) -- Research and Markets has announced the addition of the "Biopharmaceutical Contract Manufacturing Market (2nd Edition), 2017-2027" report to their offering. The Biopharmaceutical Contract Manufacturing Market (2nd edition), 2017-2027' report provides an extensive study of the contract manufacturing market for biopharmaceuticals. As the biotechnology industry continues to strive to maximize profits, outsourcing has emerged as a promising trend. The study features in-depth analysis, highlighting capabilities of a diverse set of biopharmaceutical CMOs. One of the key focus areas of the study was to estimate size of the future opportunity for biopharmaceutical CMOs over the coming decade. In order to provide a detailed future outlook, our projections have been segmented on the basis of commonly outsourced business operations (Active Pharmaceutical Ingredients (APIs) and Finished Dosage Formulations (FDFs)), types of expression systems and key geographical regions. The base year for the report is 2017, and it provides a detailed market forecast for the period between 2017 and 2027. The research, analysis and insights presented in this report is backed by a deep understanding of insights gathered both from secondary and primary sources. For the purpose of the study, we invited more than 200 senior stakeholders in the industry to participate in a survey. This enabled us to solicit their opinions on upcoming opportunities and challenges that must be considered for a more inclusive growth. In addition, the opinions and insights presented in this study were influenced by discussions conducted with several key players in this domain. The report features detailed transcripts of interviews held with Birgit Schwab (Senior Manager Strategic Marketing, Rentschler Biotechnologie), Claire Otjes (Assistant Marketing Manager, Batavia Biosciences), David C Cunningham (Director Corporate Development, Goodwin Biotechnology), Dietmar Katinger (CEO, Polymun Scientific), Kevin Daley (Director Pharmaceuticals, Novasep Synthesis), Mark Wright (Site Head, Grangemouth, Piramal Healthcare), Raquel Fortunato (CEO, GenIbet Biopharmaceuticals), Sebastian Schuck (Head of Business Development, Wacker Biotech), Stephen Taylor (Senior Vice President Commercial, FUJIFILM Diosynth Biotechnologies) and Tim Oldham (CEO, Cell Therapies). It is worth highlighting that the biopharmaceutical market is characterized by a huge unmet need for adequate manufacturing facilities and expertise. Given the inherent complexities associated with the development of biologics, the aforementioned need is likely to translate into promising business opportunities for CMOs. In addition to other elements, it provides information on the following: - The competitive market landscape and industry analysis based on a number of parameters, such as geographical location, scale of operation, type of biologics manufactured, expression systems used, type of bioreactors used, mode of operation of bioreactors and bioprocessing capacity. - Elaborate profiles of key players that have a diverse range of capabilities for the development, manufacturing and packaging of biologics. Each profile provides an overview of the company, its financial performance, information on its manufacturing service and facilities, partnerships and recent developments. - A detailed discussion on the key enablers, including certain niche sub-segments, such as ADCs, bispecific antibodies, cell therapies, gene therapies and viral vectors, which are likely to have a significant impact on the growth of the contract services market. - A case study on the growing global biosimilars market, highlighting the opportunities for biopharmaceutical contract service providers. - A detailed capacity analysis, based on global, market wide research on the individual development and manufacturing capacities of various stakeholders in the market. The analysis takes into consideration the average capacities of small, mid-sized, large and very large CMOs, and is based on robust data collection done via both secondary and primary research. - Information on other aspects of biopharmaceutical outsourcing, which include the growing number of collaborations, partnerships and investments in facility expansions. - Affiliated trends, key drivers and challenges, under a comprehensive SWOT framework, which are likely to impact the industry's evolution. Key Topics Covered: 1. Preface 2. Executive Summary 3. Introduction 4. Competitive Landscape 5. Biopharmaceutical Contract Manufacturing In North America 6. Biopharmaceutical Contract Manufacturing In Europe 7. Biopharmaceutical Contract Manufacturing In Asia And The Rest Of The World 8. Niche Sectors In Biopharmaceutical Contract Manufacturing 9. Case Study: Outsourcing Of Biosimilars 10. Recent Developments 11. Capacity Analysis 12. Survey Analysis 13. Opportunity Analysis 14. Swot Analysis 15. Future Of The Biopharmaceutical Cmo Market 16. Interview Transcripts 17. Appendix I Tabulated Data 18. Appendix Ii List Of Companies And Organizations - 3P Biopharmaceuticals - Aalto Scientific - AbbVie Contract Manufacturing - AbGenomics - Ablynx - Abzena - ACES Pharma - Acticor Biotech - Active Biotech - Adar Biotech - ADC Therapeutics - Adimab - Advanced BioScience Laboratories (ABL) - Advanced Biotherapeutics Consulting (ABC) - Affimed - Affinity Life Sciences - Agensys - Ajinomoto Althea - Albany Molecular Research (AMRI) - Alberta Cell Therapy Manufacturing - Alcami - Aldevron - Allele Biotechnology - Alliance Medical Products - Alligator Bioscience - Allozyne - ALMAC Group - Altaris Capital Partners - AmatsiQBiologicals - AmbioPharm - Ambrx - AmBTU - AMEGA Biotech - Amgen - Amneal Life Sciences - AMSBIO - Anogen - apceth Biopharma - Applied Biological Materials - Applied Viromics - Aptuit - Arabio - Asahi Glass - Aspyrian Therapeutics - Astellas Pharma - AstraZeneca - Asymchem - Athenex Pharma Solutions - Atlantic Bio GMP - AURA Biotechnologies - AUSTRIANOVA - AutekBio - Avecia - Avid Biologics - Avid Bioservices - Bachem - Baliopharm - Batavia Biosciences - Baxter BioPharma Solutions - Bayer - BCN Peptides - Beckman Research Institute - Beijing ABT Genetic Engineering Technology - Bharat Serums And Vaccines - BIBITEC - Bicycle Therapeutics - BINEX - Bio Elpida - Bioanalytical Sciences Department, Southern Research - BioCell - Biocon - BioConnection - Biofabri - Biogen-Idec - BioLineRx - Biological and Cellular GMP Manufacturing Facility, City of Hope - Biological E - Biological Process Development Facility, University of Nebraska - BioMARC - Biomatik - Biomay - BIOMEVA - BiondVax Pharmaceuticals - BioPharmaceuticals Australia - Biosynergy - Bio-Synthesis - BioTechLogic - BioTechnique - Biotechpharma - Biotecnol - Biotest - BioVectra - Biovian - Blue Stream Laboratories - Boehringer Ingelheim - Boehringer Ingelheim BioXcellence - Brammer Bio - Bristol-Myers Squibb - Bryllan - BSP Pharmaceuticals - Cambrex - CARBOGEN AMCIS - Catalent - Catalent Biologics - Catalent Pharma Solutions - Cedarburg Pharmaceuticals - Celgene - Cell and Gene Therapy Catapult - Cell Culture Company - Cell Essentials - Cell Therapies - Cell Therapy and Regenerative Medicine, University of Utah - Celldex Therapeutics - CELLforCURE - Cellin Technologies - Cells for Sight, Stem Cell Therapy Research Unit, University College London - Celltrion - Cellular Dynamics International (a FUJIFILM company) - Cellular Therapeutics - Cellular Therapy Integrated Service, Case Western Reserve University - Celonic - Center for Biocatalysis and Bioprocessing, University of Iowa - Center for Biomedical Engineering and Advanced Manufacturing, McMaster University - Center for Cell and Gene Processing, Takara Bio - Center for Cell and Gene Therapy, Baylor College of Medicine - Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia (CHOP) - Center of iPS Cell Research and Application, Kyoto University (CiRA) - Centre for Commercialization of Regenerative Medicine - Centrose - Century Pharmaceuticals - Cerbios-Pharma - CEVEC Pharmaceuticals - Charles River Laboratories - ChemCon - Chemi Peptides - ChemPartner - Children's GMP / GMP facility St. Jude Children's Research Hospital - ChromaCon - Cincinnati Children's Hospital Medical Center - CinnaGen - Clinical Biomanufacturing Facility, University of Oxford - Clinical Research Facility, South London and Maudsley - CMC Biologics - Cobra Biologics - Cognate BioServices - Coldstream Laboratories - Concord Biotech - Concortis - Cook Pharmica - Corden Pharma - Covance - Creative Biogene - Creative Biolabs - Cryosite - CytomX Therapeutics - Cytovance Biologics - Daiichi Sankyo - Dalton Pharma Services - Dishman Group - DMBio - Dow Pharmaceutical Solutions - Dutalys - EirGenix - Eli Lilly - Embio - EMD Serono - Emergent BioSolutions - Emerson - Encap Drug Delivery - Endo Pharmaceuticals - Epigen Biotech - Esperance Pharmaceuticals - EuBiologics - EUCODIS Bioscience - EUFETS - Eurofins Central Global Laboratory - Eurogentec - Euticals - Evonik - Fabion Pharmaceuticals - Ferro Pfanstiehl - FinVector - Formation Biologics - Formosa Laboratories - Foundation BioPharma - Fraunhofer Institute for Cell Therapy and Immunology IZI - French National Centre for Scientific Research, Université de Toulouse - Frontage Laboratories - F-star - FUJIFILM Diosynth Biotechnologies - Fusimab - Fusion Antibodies - Gadea Pharmaceutical Group - Gala Biotech - Gallus BioPharmaceuticals - Ganymed Pharmaceuticals - Gates Biomanufactuirng Facility - GE Healthcare - GEG Tech - Gene and Cell Therapy Lab, Institute of Translational Health Sciences - Gene Medicine Japan / Kobe Biomedical Accelerator - Gene Transfer Vector Core (GTVC) - Gene Transfer Vector Core, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary - Gene Transfer, Targeting and Therapeutics Core, Salk Institute for Biological Studies - Gene Vector and Virus Core, Stanford Medicine - GeneCure Biotechnologies - GeneDetect - Genentech - Genethon - GenIbet Biopharmaceuticals - Genmab - Génopoïétic - GenVec - Gilead Sciences - GIPharma - Glenmark Pharmaceuticals - Glycotope Biotechnology - GNH India - Goodwin Biotechnology - GOSH Cellular Therapy Laboratories, University College of London - GP Pharm - Grand River Aseptic Manufacturing - Great Point Partners - GreenPak Biotech - Grünenthal - GSEx, The Robinson Research Institute, University of Adelaide - GSK - GSK-Domantis - GTP Technology - Guy's and St Thomas' Facility - HALIX - Harvest Moon Pharmaceuticals - Health Biotech - Health Sciences Authority - Heidelberg Pharma - Hepalink - Hetero Drugs - Histocell - Hisun Pharmaceuticals USA - Ho Research Consortium - Hong Kong Institute of Biotechnology - Hope Center Viral Vectors Core, Washington University School of Medicine - iBIOSOURCE - Icagen - IDDI - IDT Biologika - Igenica Biotherapeutics - ImClone Systems - ImmunoGen - Immunomedics - INC Research - Indian Immunologicals - Inhibrx - Inno Biologics - Innovent Biologics - Intas Pharmaceuticals - Integrity Bio - International Joint Cancer Institute, Military Medical University - Intertek - Istituto Biochimico Italiano Giovanni Lorenzini - JHL Biotech - John Goldmann Centre for Cellular Therapy, Imperial College London - Julphar Gulf Pharmaceutical Industries - KABS Pharmaceutical Services - Kairos Therapeutics - Kamat Pharmatech - KBI Biopharma - Kemwell Biopharma - Laboratory for Cell and Gene Medicine, Stanford University - LAMPIRE Biological Laboratories - Lentigen Technology (wholly owned subsidiary of Miltenyi Biotec) - LFB BIOMANUFACTURING - Lindis Biotech - Lonza - LuinaBio - MabPlex - MacroGenics - Maine Biotechnology Services - MassBiologics - MaSTherCell - MBI International - MediaPharma - MedImmune - Medix Biochemica - Menarini Biotech - Merck - Meridian Life Science - Merrimack - Merro Pharmaceutical - Mersana Therapeutics - Merus - MGH Vector Core (Massachusetts General Hospital Neuroscience Center) - MicroBiopharm Japan - Microbix Biosystems - Millennium Pharmaceuticals - Minomic International - Mitsubishi Gas Chemical Company - Moderna Therapeutics - Molecular and Cellular Therapeutics, University of Minnesota - Molecular Partners - MolMed - MPI Research - Multispan - Mycenax Biotech - Nantes Gene Therapy Institute - Nascent Biologics - National Cancer Institute (NCI) - National Research Council of Canada - NBE Therapeutics - Neuland Laboratories - NeuroCure (Viral Core Facility) - NeuroFx - Newcastle Cellular Therapies, University of Newcastle - NextCell - NHS Blood and Transplant - NHSBT Birmingham - Nikon Cell And Gene Therapy Contract Manufacturing - Nitto Avecia Pharma Services - Nordic Nanovector - Norwegian Institute of Public Health - Nova Laboratories - Novartis - Novasep - Novex Innovations - NovImmune - Numab - Oasmia Pharmaceutical - OcellO - OctoPlus - Okairos (GSK subsidiary) - Olon - Omnia Biologics - OncoMed - OncoQuest - OsoBio - OXB Solutions (a business of Oxford BioMedica) - Oxford BioMedica - Oxford BioTherapeutics - Oxford Genetics - Pacific GMP - Paktis Antibody Services - Palatin Technologies - Pamlico BioPharma - Panacea Biotec - Paragon Bioservices - Parexel - Particle Sciences - PATH - Patheon - PCI Services (Biotec Services International) - PCT, a Caladrius company - Penn Vector Core, University of Pennsylvania - Pfizer - Pfizer CentreOne - PharmAbcine - PharmaBio - PharmaCell - Pharmedartis - PharmiCell - Philip S Orsino Facility for Cell Therapy, Princess Margaret Hospital - Philochem - PhotoBiotics - Pierre Fabre - Piramal Pharma Solutions - PlasmidFactory - Polymun Scientific - Polypeptide Group - Praxis Pharmaceutical - Precision Antibody - Precision Biologics - PREMAS Biotech - ProBioGen - Productos Bio-Logicos - Profectus BioSciences - Progenics Pharmaceuticals - ProJect Pharmaceutics - ProMab Biotechnologies - Protheragen - Provantage End-to-End Services (Merck Millipore) - PX'Therapeutics - Pyramid Labs - Quintiles - Raymond G Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia - Rayne's Cell Therapy Suite, King's College London - Receptor Logic - Redwood Bioscience - Regeneron Pharmaceuticals - Reliance Life Sciences - Rentschler Biotechnologie - Research and Development Center for Cell Therapy, Foundation for Biomedical Research and Innovation - Richter-Helm BioLogics - Rimedion - Robertson Clinical and Translational Cell Therapy, Duke University - Roche - Roslin Cell Therapies - Roswell Park Cancer Institute - Royal DSM - Royal Free, CCGTT - SAB Technology - SAFC - Samsung BioLogics - Sandoz - Sanofi, CEPiA (Commercial & External Partnership, Industrial Affairs) - Sanofi-Aventis - Sanquin Pharmaceutical Services - School of Medicine, University of Utah - Scientific Protein Laboratories - Sea Lane Biotechnologies - Seattle Genetics - Selexys Pharmaceuticals - Senn Chemicals - SGS Life Science Services - Shire - SignaGen Laboratories - Singota Solutions - Sirion Biotech - SNBTS Cellular Therapy Facility - Societa Italiana Corticosteroidi - Sorrento Therapeutics - Spirogen - ST Pharm - Stem CentRx - Sutro Biopharma - Sydney Cell and Gene Therapy - Symbiosis Pharmaceutical Services - Symbiosis, the Analytical Company - SynCo Bio Partners - Synergys Biotherapeutics - Syngene - SYNIMMUNE - Synthon - Sypharma - System Biosciences - Takara Bio - Takeda - The Chemistry Research Solution - The Lentiviral Laboratory, USC School of Pharmacy - The Native Antigen Company - The Vector Core, University of North Carolina - Therapure Biopharma (Therapure Biomanufacturing) - THERAVECTYS - Thermo Fisher Scientific - Toyobo Biologics - Translational Sciences - TranXenoGen - Trenzyme - Trion Pharma - Triphase Accelerator Corporation - UC Davis GMP Laboratory - UCB-Celltech - UCLA Human Gene and Cell Therapy - UMN Pharma - University of Alabama Fermentation Facility - University of Manchester - University of Oxford Clinical BioManufacturing Facility - University of Texas - Upstate Stem Cell cGMP Facility, University of Rochester - Valerion Therapeutics - Valneva - Vectalys - Vector Biolabs - Vector Core / GMP Facility, UC Davis - Vector Core Lab / Human Applications Lab, Powell Gene Therapy Center, University of Florida - Vector Core of Gene Therapy Laboratory of Nantes - Vector Production Facility, Indiana University - Vecura (Karolinska University Hospital ) - Vetter Pharma International - VGXI - Vibalogics - Vigene Biosciences - Viral Vector Core / Clinical Manufacturing Facility, Nationwide Children's Hospital - Viral Vector Core, Duke University - Viral Vector Core, Sanford Burnham Prebys Medical Discovery Institute - Viral Vector Core, University of Iowa Carver College of Medicine - Viral Vector Core, University of Massachusetts Medical School (UMMS) - Virovek - Vista Biologicals - VIVEbioTECH - Wacker Biotech - Waisman Biomanufacturing - WIL Research - Wockhardt - Wolfson Gene Therapy Unit, University College of London - WuXi AppTec - Wyeth - X-BODY Biosciences - Xellbiogene - Xencor - YposKesi - Zhejiang HISUN Pharmaceuticals - Zhengyang Gene Technology - Zumutor Biologics - Zydus Cadila - Zymeworks - ZymoGenetics - Zyngenia For more information about this report visit https://www.researchandmarkets.com/research/m9qmm2/biopharmaceutical


News Article | October 25, 2016
Site: www.nature.com

Strains of P. falciparum (Dd2, 3D7, D6, K1, NF54, V1/3, HB3, 7G8, FCB and TM90C2B) were obtained from the Malaria Research and Reference Reagent Resource Center (MR4). PfscDHODH, the transgenic P. falciparum line expressing S. cerevisiae DHODH19, was a gift from A. B. Vaidya. P. falciparum isolates were maintained with O-positive human blood in an atmosphere of 93% N , 4% CO , 3% O at 37 °C in complete culturing medium (10.4 g l−1 RPMI 1640, 5.94 g l−1 HEPES, 5 g l−1 albumax II, 50 mg l−1 hypoxanthine, 2.1 g l−1 sodium bicarbonate, 10% human serum and 43 mg l−1 gentamicin). Parasites were cultured in medium until parasitaemia reached 3–8%. Parasitaemia was determined by checking at least 500 red blood cells from a Giemsa-stained blood smear. For the compound screening, a parasite dilution at 2.0% parasitaemia and 2.0% haematocrit was created with medium. 25 μl of medium was dispensed into 384-well black, clear-bottom plates and 100 nl of each compound in DMSO was transferred into assay plates along with the control compound (mefloquine). Next, 25 μl of the parasite suspension in medium was dispensed into the assay plates giving a final parasitaemia of 1% and a final haematocrit of 1%. The assay plates were incubated for 72 h at 37 °C. 10 μl of detection reagent consisting of 10× SYBR Green I (Invitrogen; supplied in 10,000× concentration) in lysis buffer (20 mM Tris-HCl, 5 mM EDTA, 0.16% (w/v) Saponin, 1.6% (v/v) Triton X-100) was dispensed into the assay plates. For optimal staining, the assay plates were left at room temperature for 24 h in the dark. The assay plates were read with 505 dichroic mirrors with 485 nm excitation and 530 nm emission settings in an Envision (PerkinElmer). High-throughput screening hits were hierarchically clustered by structural similarity using average linkage on pairwise Jaccard distances43 between ECFP4 fingerprints44. Pipeline Pilot45 was used for fingerprint and distance calculation; clustering and heat-map generation was done in R (ref. 46). HepG2 cells (ATCC) were maintained in DMEM, 10% (v/v) FBS (Sigma), and 1% (v/v) antibiotic–antimycotic in a standard tissue culture incubator (37 °C, 5% CO ). P. berghei (ANKA GFP–luc) infected A. stephensi mosquitoes were obtained from the New York University Langone Medical Center Insectary. For assays, ∼17,500 HepG2 cells per well were added to a 384-well microtitre plate in duplicate. After 18–24 h at 37 °C the media was exchanged and compounds were added. After 1 h, parasites obtained from freshly dissected mosquitoes were added to the plates (4,000 parasites per well), the plates were spun for 10 min at 1,000 r.p.m. and then incubated at 37 °C. The final assay volume was 30 μl. After a 48-h incubation at 37 °C, Bright-Glo (Promega) was added to the parasite plate to measure relative luminescence. The relative signal intensity of each plate was evaluated with an EnVision (PerkinElmer) system. Micropatterned co-culture (MPCC) is an in vitro co-culture system of primary human hepatocytes organized into colonies and surrounded by supportive stromal cells. Hepatocytes in this format maintain a functional phenotype for up to 4–6 weeks without proliferation, as assessed by major liver-specific functions and gene expression47, 48, 49. In brief, 96-well plates were coated homogenously with rat-tail type I collagen (50 μg ml−1) and subjected to soft-lithographic techniques to pattern the collagen into 500-μm-island microdomains that mediate selective hepatocyte adhesion. To create MPCCs, cryopreserved primary human hepatocytes (BioreclamationIVT) were pelleted by centrifugation at 100g for 6 min at 4 °C, assessed for viability using Trypan blue exclusion (typically 70–90%), and seeded on micropatterned collagen plates (each well contained ~10,000 hepatocytes organized into colonies of 500 μM) in serum-free DMEM with 1% penicillin–streptomycin. The cells were washed with serum-free DMEM with 1% penicillin–streptomycin 2–3 h later and replaced with human hepatocyte culture medium48. 3T3-J2 mouse embryonic fibroblasts were seeded (7,000 cells per well) 24 h after hepatocyte seeding. 3T3-J2 fibroblasts were courtesy of H. Green50. MPCCs were infected with 75,000 sporozoites (NF54) (Johns Hopkins University) 1 day after hepatocytes were seeded48, 49. After incubation at 37 °C and 5% CO for 3 h, wells were washed once with PBS, and the respective compounds were added. Cultures were dosed daily. Samples were fixed on day 3.5 after infection. For immunofluorescence staining, MPCCs were fixed with −20 °C methanol for 10 min at 4 °C, washed twice with PBS, blocked with 2% BSA in PBS, and incubated with mouse anti-P. falciparum Hsp70 antibodies (clone 4C9, 2 μg ml−1) for 1 h at room temperature. Samples were washed with PBS then incubated with Alexa 488-conjugated secondary goat anti-mouse for 1 h at room temperature. Samples were washed with PBS, counterstained with the DNA dye Hoechst 33258 (Invitrogen; 1:1,000), and mounted on glass slides with fluoromount G (Southern Biotech). Images were captured on a Nikon Eclipse Ti fluorescence microscope. Diameters of developing liver stage parasites were measured and used to calculate the corresponding area. All rhesus macaques (Macaca mulatta) used in this study were bred in captivity for research purposes, and were housed at the Biomedical Primate Research Centre (BPRC; AAALAC-certified institute) facilities under compliance with the Dutch law on animal experiments, European directive 86/609/EEC and with the ‘Standard for Humane Care and Use of Laboratory Animals by Foreign Institutions’ identification number A5539-01, provided by the Department of Health and Human Services of the US National Institutes of Health. The local independent ethical committee first approved all protocols. Non-randomized rhesus macaques (male or female; 5−14 years old; one animal per month) were infected with 1 × 106 P. cynomolgi (M strain) blood-stage parasites, and bled at peak parasitaemia. Approximately 300 female A. stephensi mosquitoes (Sind-Kasur strain, Nijmegen University Medical Centre St Radboud) were fed with this blood as described previously51. Rhesus monkey hepatocytes were isolated from liver lobes as described by previously52. Sporozoite infections were performed within 3 days of hepatocyte isolation. Sporozoite inoculation of primary rhesus monkey hepatocytes was performed as described previously53, 54. On day 6, intracellular P. cynomolgi malaria parasites were fixed, stained with purified rabbit antiserum reactive against P. cynomolgi Hsp70.1 (ref. 53), and visualized with FITC-labelled goat anti-rabbit IgG antibodies. Quantification of small ‘hypnozoite’ exoerythrocytic forms (1 nucleus, a small round shape, a maximal diameter of 7 μm) or large ‘developing parasite’ exoerythrocytic forms (more than 1 nucleus, larger than 7 μm and round or irregular shape) was determined for each well using a high-content imaging system (Operetta, PerkinElmer). P. falciparum 3D7 stage IV–V gametocytes were isolated by discontinuous Percoll gradient centrifugation of parasite cultures treated with 50 mM N-acetyl-d-glucosamine for 3 days to kill asexual parasites. Gametocytes (1.0 × 105) were seeded in 96-well plates and incubated with compounds for 72 h. In vitro anti-gametocyte activity was measured using CellTiter-Glo (Promega). A detailed description of the method is published elsewhere55. In brief, NF54pfs16-LUC-GFP highly synchronous gametocytes were induced from a single intra-erythrocytic asexual replication cycle. On day 0 of gametocyte development, spontaneously generated gametocytes were removed by VarioMACS magnetic column (MAC) technology. Early stage I gametocytes were collected on day 2 of development and late-stage gametocytes (stage IV) on day 8 using MAC columns. Percentage parasitaemia and haematocrit was adjusted to 10 and 0.1, respectively. 45 μl of parasite sample were added to PerkinElmer Cell carrier poly-d-lysine imaging plates containing 5 μl of test compound at 16 doses, including control wells containing 4% DMSO and 50 μM puromycin (0.4% and 5 μM final concentrations, respectively), the plates sealed with a membrane (Breatheasy or 4ti-05 15/ST) and incubated for 72 h in standard incubation conditions of 5% CO , 5% O , 90% N and 60% humidity at 37 °C. After incubation, 5 μl of 0.07 μg ml−1 MitoTracker Red CM-H2XRos (MTR) (Invitrogen) in PBS was added to each well, and plates were resealed with membranes and incubated overnight under standard conditions. The following day, the plates were brought to room temperature for at least one hour before being measured on the Opera QEHS Instrument. Image analysis was performed using an Acapella (PerkinElmer)-based algorithm that identifies gametocytes of the expected morphological shape with respect to degree of elongation and specifically those parasites that are determined as viable by the MitoTracker Red CM-H2XRos fluorescence size and intensity. IC values were determined using GraphPad Prism 4, using a 4-parameter log dose, nonlinear regression analysis, with sigmoidal dose–response (variable slope) curve fit. P. falciparum transmission-blocking activity of BRD7929 was assessed in a standard membrane feeding assay as previously described56. In brief, P. falciparumNF54 hsp70-GFP-luc reporter parasites were cultured up to stage V gametocytes (day 14). Test compounds were serially diluted in DMSO and subsequently in RPMI medium to reach a final DMSO concentration of 0.1%. Diluted compound was either pre-incubated with stage V gametocytes for 24 h (indirect mode) or directly added to the blood meal (direct mode). Gametocytes were adjusted to 50% haematocrit, 50% human serum and fed to A. stephensi mosquitoes. All compound dilutions were tested in duplicate in independent feeders. After 8 days, mosquitoes were collected and the relative decrease in oocysts density in the midgut was determined by measurement of luminescence signals in 24 individual mosquitoes from each cage. For each vehicle (control) cage, an additional 10 mosquitoes were dissected and examined by microscopy to determine the baseline oocyst intensity. In vitro resistance selections were performed as previously described15. In brief, approximately 1 × 109 P. falciparum Dd2 parasites were treated with 60 nM (EC ) or 150 nM (10 × EC ) of BRD1095 in each of four independent flasks for 3–4 days. After the compounds were removed, the cultures were maintained in compound-free complete RPMI growth medium with regular media exchange until healthy parasites reappeared. Once parasitaemia reached 2–4%, compound pressure was repeated and these steps were executed for about 2 months until the initial EC shift was observed. Three out of four independent selections pressured at 60 nM developed a phenotypic EC shift. None of the selections pressured at 150 nM resulted in resistant parasites. After an initial shift in the dose–response phenotype was observed, selection at an increased concentration was repeated in the same manner until at least a threefold shift in EC was observed. Selected parasites were then cloned by limiting dilution. BRD73842-resistant selections were conducted in a similar manner except that parasites were initially treated at 0.5 μM (10× EC ) for 4 days or 150 nM (EC ) for 2 days in each of two independent flasks. The Y1356N mutant was derived from a flask pressured at 0.5 μM and the L1418F mutant was developed from one of the flasks exposed to the 150 nM. DNA libraries were prepared for sequencing using the Illumina Nextera XT kit (Illumina), and quality-checked before sequencing on a Tapestation. Libraries were clustered and run as 100-bp paired-end reads on an Illumina HiSeq 2000 in RapidRun mode, according to the manufacturer’s instructions. Samples were analysed by aligning to the P. falciparum 3D7 reference genome (PlasmoDB v. 11.1). To identify SNVs and CNVs, a sequencing pipeline developed for P. falciparum (Plasmodium Type Uncovering Software, Platypus) was used as previously described, with the exception of an increase in the base quality filter from 196.5 to 1,000 (ref. 57). Substrate-dependent inhibition of recombinant P. falciparum DHODH protein was assessed in an in vitro assay in 384-well clear plates (Corning 3640) as described previously58. A 20-point dilution series of inhibitor concentrations were assayed against 2–10 nM protein with 500 μM l-dihydroorotate substrate (excess), 18 μM dodecylubiquinone electron acceptor (~K ), and 100 μM 2,6-dichloroindophenol indicator dye in assay buffer (100 mM HEPES pH 8.0, 150 mM NaCl, 5% glycerol, 0.5% Triton X-100). Assays were incubated at 25 °C for 20 min and then assessed via OD . Data were normalized to 1% DMSO and excess inhibitor (25 μM DSM265; ref. 7). Substrate-dependent inhibition of recombinant human DHODH protein was assessed in an in vitro assay in 384-well clear plates (Corning 3640) as described previously59. A 20-point dilution series of inhibitor concentrations was assayed against 13 nM protein with 1 mM l-dihydroorotate substrate (excess), 100 μM dodecylubiquinone electron acceptor, and 60 μM 2,6-dichloroindophenol indicator dye in assay buffer (50 mM Tris HCl pH 8.0, 150 mM KCl, 0.1% Triton X-100). Assays were incubated at 25 °C for 20 min and then assessed via OD . Data were normalized to 1% DMSO and no enzyme. The synthetic gene for full-length P. vivax PI4K (PVX_098050) was synthesized from GeneArt (ThermoScientific), and was expressed and purified as previously described20. Aliquots of P. vivax PI4Kβ were flash-frozen in liquid nitrogen and stored at −80°C. Full-length human PI4KB (uniprot gene Q9UBF8-2) was expressed and purified as previously described60. 100 nM extruded lipid vesicles were made to mimic Golgi organelle vesicles (20% phosphatidylinositol, 10% phosphatidylserine, 45% phosphatidylcholine and 25% phosphatidylethanolamine) in lipid buffer (20 mM HEPES pH 7.5 (room temperature), 100 mM KCl, 0.5 mM EDTA). Lipid kinase assays were carried out using the Transcreener ADP2 FI Assay (BellBrook Labs) following the published protocol as previously described61. 4-μl reactions ran at 21 °C for 30 min in a buffer containing 30 mM HEPES pH 7.5, 100 mM NaCl, 50 mM KCl, 5 mM MgCl , 0.25 mM EDTA, 0.4% (v/v) Triton X-100, 1 mM TCEP, 0.5 mg ml−1 Golgi-mimic vesicles and 10 μM ATP. P. vivax PI4Kβ was used at 7.5 nM and human PI4KB was used at 200 nM. Fluorescence intensity was measured using a Spectramax M5 plate reader with excitation at 590 nm and emission at 620 nm (20-nm bandwidth). IC values were calculated from triplicate inhibitor curves using GraphPad Prism software. The model was built using the SWISS-MODEL online resource62, 63, 64 and Prime65 (Schrödinger Release 2015-2: Prime, version 4.0, Schrödinger), with human PheRS (PDB accession 3L4G) as a template for P. falciparum PheRS (PlasmoDB Gene ID: PF3D7_0109800). The template was chosen based on highest sequence identity and similarity identified via PSI-BLAST. Target-template alignment was made using ProMod-II and validated with Prime STA. Coordinates from residues that were conserved between the target and the template were copied from the template to the model, and remaining sites were remodelled using segments from known structures. The side chains were then rebuilt, and the model was finally refined using a force field. Protein sequences of both α- (PF3D7_0109800) and β- (PF3D7_1104000) subunits of cytoplasmic P. falciparum PheRS were obtained from PlasmoDB ( http://plasmodb.org/plasmo/). Full length α- and β-subunit gene sequences optimized for expression in E. coli were cloned into pETM11 (Kanamycin resistance) and pETM20 (ampicillin resistance) expression vectors using Nco1 and Kpn1 sites and co-transformed into E. coli B834 cells. Protein expression was induced by addition of 0.5 mM isopropyl β-d-1-thiogalactopyranoside (IPTG) and cells were grown until an OD of 0.6–0.8 was reached at 37 °C. They were then allowed to grow at 18 °C for 20 h after induction. Cells were separated by centrifugation at 5,000g for 20 min and the bacterial pellets were suspended in a buffer consisting of 50 mM Tris–HCl (pH 7.5), 200 mM NaCl, 4 mM β-mercaptoethanol, 15% (v/v) glycerol, 0.1 mg ml−1 lysozyme and 1 mM phenylmethylsulfonyl fluoride (PMSF). Cells were lysed by sonication and cleared by centrifugation at 20,000g for 1 h. The supernatant was applied on to prepacked NiNTA column (GE Healthcare), and bound proteins were eluted by gradient-mixing with elution buffer (50 mM Tris–HCl (pH 7.5), 80 mM NaCl, 4 mM β-mercaptoethanol, 15% (v/v) glycerol, 1 M imidazole). Pure fractions were pooled and loaded on to heparin column for further purification. Again, bound proteins were eluted using gradient of heparin elution buffer 50 mM Tris–HCl (pH 7.5), 1 M NaCl, 4 mM β-mercaptoethanol, 15% (v/v) glycerol). Pure fractions were again pooled and dialysed overnight into a buffer containing 50 mM Tris–HCl (pH 7.5), 200 mM NaCl, 4 mM β-mercaptoethanol, 1 mM DTT and 0.5 mM EDTA. TEV protease (1:50 ratio of protease:protein) was added to the protein sample and incubated at 20 °C for 24 h to remove the polyhistidine tag. Protein was further purified via gel-filtration chromatography on a GE HiLoad 60/600 Superdex column in 50 mM Tris–HCl (pH 7.5), 200 mM NaCl, 4 mM β-mercaptoethanol, 1 mM MgCl . The eluted protein (a heterodimer of P. falciparum cPheRS) were collected, assessed for purity via SDS–PAGE and stored at −80 °C. Nuclear encoded tRNAPhe from P. falciparum was synthesized using an in vitro transcription method as described earlier22, 66. Aminoacylation and enzyme inhibition assays for P. falciparum cytosolic PheRS were performed as described earlier22, 67. Enzymatic assays were performed in buffer containing 30 mM HEPES (pH 7.5), 150 mM NaCl, 30 mM KCl, 50 mM MgCl , 1 mM DTT, 100 μM ATP, 100 μM l-phenylalanine, 15 μM P. falciparum tRNAPhe, 2 U ml−1 E. coli inorganic pyrophosphatase (NEB) and 500 nM recombinant P. falciparum PheRS at 3 °C. Reactions at different time points were stopped by the addition of 40 mM EDTA and subsequent transfer to ice. Recombinant maltose binding protein was used as negative control. The cPheRS inhibition assays were performed using inhibitor concentrations of 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, 5 μM and 10 μM for strong binders and 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM and 500 μM for weaker binders in the assay buffer. Enzymatic and inhibition experiments were performed twice in triplicate. Mammalian cells (HepG2, A549, and HEK293) were obtained from the ATCC and cultured routinely in DMEM with 10% FBS and 1% (v/v) antibiotic–antimycotic. For cytotoxicity assays, 1 × 106 cells were seeded into 384-well plates 1 day before compound treatment. Cells were treated with ascending doses of compound for 72 h, and viability was measured using Cell-Titer Glo (Promega). All cell lines were tested for Mycoplasma contamination using Universal mycoplasma Detection Kit (ATCC). In vitro characterization assays (protein binding, microsomal stability, hepatocyte stability, cytochrome P450 (CYP) inhibition, and aqueous solubility) were performed according to industry-standard techniques. Ion channel inhibition studies were performed using the Q-Patch system using standard techniques. All animal experiments were conducted in compliance with institutional policies and appropriate regulations and were approved by the institutional animal care and use committees for each of the study sites (the Broad Institute, 0016-09-14; Harvard School of Public Health, 03228; Eisai, 13-05, 13-07, 14-C-0027). No method of randomization or blinding was used in this study. CD-1 mice (n = 4 per experimental group; female; 6–7-week-old; 20–24 g, Charles River) were intravenously inoculated with approximately 1 × 105 P. berghei (ANKA GFP-luc) blood-stage parasites 24 h before treatment and compounds were administered orally (at 0 h). Parasitaemia was monitored by the in vivo imaging system (IVIS SpectrumCT, Perkinelmer) to acquire the bioluminescence signal (150 mg kg-1 of luciferin was intraperitoneally injected approximately 10 min before imaging). In addition, blood smear samples were obtained from each mouse periodically, stained with Giemsa, and viewed under a microscope for visual detection of blood parasitaemia. Animals with parasitaemia exceeding 25% were humanely euthanized. CD-1 mice (n = 4 per experimental group; female; 6–7-week-old; 20–24 g, Charles River) were inoculated intravenously with approximately 1 × 105 P. berghei (ANKA GFP-luc) sporozoites freshly dissected from A. stephensi mosquitoes. Immediately after infection, the mice were treated with single oral doses of BRD7929; infection was monitored as described for the P. berghei erythrocytic-stage assay. For time-course experiments, the time of compound treatment (single oral dose of 10 mg kg−1) was varied from 5 days before infection to 2 days after infection. CD-1 (n = 3 per experimental group; female; 6–7-week-old; 21–24 g, Charles River) mice were infected with P. berghei (ANKA GFP-luc) for 96 h before treatment with vehicle or BRD7929 (day 0). On day 2, female A. stephensi mosquitoes were allowed to feed on the mice for 20 min. After 1 week (day 9), the midguts of the mosquitoes were dissected out and oocysts were enumerated microscopically (12.5× magnification). In vivo adapted P. falciparum (3D7HLH/BRD) were selected as described previously68. In brief, NSG mice (n = 2 per experimental group; female; 4–5-week-old; 19–21 g; The Jackson Laboratory) were intraperitoneally injected with 1 ml of human erythrocytes (O-positive, 50% haematocrit, 50% RPMI 1640 with 5% albumax) daily to generate mice with humanized circulating erythrocytes (huRBC NSG). Approximately 2 × 107 blood-stage P. falciparum 3D7HLH/BRD (ref. 69) were intravenously infected to huRBC NSG mice and >1% parasitaemia was achieved 5 weeks after infection. After three in vivo passages, the parasites were frozen and used experimentally. Approximately 48 h after infection with 1 × 107 blood-stage of P. falciparum 3D7HLH/BRD, the mean parasitaemia was approximately 0.4%. huRBC NSG mice were orally treated with a single dose of compound and parasitaemia was monitored for 30 days by IVIS to acquire the bioluminescence signal (150 mg kg-1 of luciferin was intraperitoneally injected approximately 10 min before imaging). huRBC NSG mice (n = 2 per experimental group; female; 4–5-week-old; 18–20 g; Jackson Laboratory) were infected with blood-stage P. falciparum 3D7HLH/BRD for 2 weeks to allow the development of mature gametocytes. Subsequently, the mice were treated with a single oral dose of BRD7929. Blood samples were collected for 11 days. For molecular detection of parasite stages, 40 μl of blood was obtained from control and treated mice. In brief, total RNA was isolated from blood samples using RNeasy Plus Kit with genomic DNA eliminator columns (Qiagen). First-strand cDNA synthesis was performed from extracted RNA using SuperScript III First-Strand Synthesis System (Life Technologies). Parasite stages were quantified using a stage-specific qRT–PCR assay as described previously33, 69. Primers were designed to measure transcript levels of PF3D7_0501300 (ring stage parasites), PF3D7_1477700 (immature gametocytes) and PF3D7_1031000 (mature gametocytes). Primers for PF3D7_1120200 (P. falciparum UCE) transcript were used as a constitutively expressed parasite marker. The assay was performed using cDNA in a total reaction volume of 20 μl, containing primers for each gene at a final concentration of 250 nM. Amplification was performed on a Viia7 qRT–PCR machine (Life Technologies) using SYBR Green Master Mix (Applied Biosystems) with the following reaction conditions: 1 cycle × 10 min at 95 °C and 40 cycles × 1 s at 95 °C and 20 s at 60 °C. Each cDNA sample was run in triplicate and the mean C value was used for the analysis. C values obtained above the cut-off (negative control) for each marker were considered negative for the presence of specific transcripts. Blood samples from each mouse before parasite inoculation were also tested for ‘background noise’ using the same primer sets. No amplification was detected from any samples. FRG knockout on C57BL/6 (human repopulated, >70%) mice (huHep FRG knockout; n = 2 per experimental group; female; 5.5–6-month-old; 19–21 g; Yecuris) were inoculated intravenously with approximately 1 × 105 P. falciparum (NF54HT-GFP-luc) sporozoites and BRD7929 was administered as a single 10 mg kg−1 oral dose one day after inoculation31. Infection was monitored daily by IVIS. Daily engraftment of human erythrocytes (0.4 ml, O-positive, 50% haematocrit, 50% RPMI 1640 with 5% albumax) was initiated 5 days after inoculation. For qPCR analysis, blood samples (40 μl) were collected 7 days after inoculation. For molecular detection of the blood-stage parasite, 40 μl of blood was obtained from control and treated mice. In brief, total RNA was isolated from blood samples using RNeasy Plus Kit with genomic DNA eliminator columns (Qiagen). First-strand cDNA synthesis was performed from extracted RNA using SuperScript III First-Strand Synthesis System (Life Technologies). The presence of the blood-stage parasites was quantified using a highly stage-specific qRT–PCR assay as described previously33, 70. Primers were designed to measure transcript levels of PF3D7_1120200 (P. falciparum UCE). The assay was performed using cDNA in a 20 μl total reaction volume containing primers for each gene at a final concentration of 250 nM. Amplification was performed on a Viia7 qRT–PCR machine (Life Technologies) using SYBR Green Master Mix (Applied Biosystems) and the reaction conditions are as follows: 1 cycle × 10 min at 95 °C and 40 cycles × 1 s at 95 °C and 20 s at 60 °C. Each cDNA sample was run in triplicate and the mean C value was used for the analysis. C values obtained above the cut-off (negative control) for each marker were considered negative for presence of specific transcripts. Blood samples from each mouse were also tested for background noise using the same primer sets before parasite inoculation. No amplification was detected from any samples. In vitro cultures of P. falciparum Dd2, with the initial inocula ranging from 105 to 109 parasites, were maintained in complete medium supplemented with 20 nM of BRD7929 (EC against Dd2). Media was replaced with fresh compound added daily and cultures monitored for 60 days to identify propensity for recrudescent parasitaemia as described34. Atovaquone was used as a control (EC  = 2 nM). Solubility was determined in PBS pH 7.4 with 1% DMSO. Each compound was prepared in triplicate at 100 μM in both 100% DMSO and PBS with 1% DMSO. Compounds were allowed to equilibrate at room temperature with a 750 r.p.m. vortex shake for 18 h. After equilibration, samples were analysed by UPLC–MS (Waters) with compounds detected by single-ion reaction detection on a single quadrupole mass spectrometer. The DMSO samples were used to create a two-point calibration curve to which the response in PBS was fit. Plasma protein binding was determined by equilibrium dialysis using the Rapid Equilibrium Dialysis (RED) device (Pierce Biotechnology) for both human and mouse plasma. Each compound was prepared in duplicate at 5 μM in plasma (0.95% acetonitrile, 0.05% DMSO) and added to one side of the membrane (200 μl) with PBS pH 7.4 added to the other side (350 μl). Compounds were incubated at 37 °C for 5 h with 350 r.p.m. orbital shaking. After incubation, samples were analysed by UPLC–MS (Waters) with compounds detected by SIR detection on a single quadrupole mass spectrometer. The required potency to inhibit the hERG channel in expressed cell lines were evaluated using an automated patch-clamp system (QPatch-HTX). Pharmacokinetics of BRD3444 and BRD1095 were performed by Shanghai ChemPartner Co. Ltd., following single intravenous and oral administrations to female CD-1 mice. BRD3444 and BRD1095 were formulated in 70% PEG400 and 30% aqueous glucose (5% in H O) for intravenous and oral dosing. Test compounds were dosed as a bolus solution intravenously at 0.6 mg kg−1 (dosing solution; 70% PEG400 and 30% aqueous glucose, 5% in H O) or dosed orally by gavage as a solution at 1 mg kg−1 (dosing solution; 70% PEG400 and 30% aqueous glucose, 5% in H O) to female CD-1 mice (n = 9 per dose route). Pharmacokinetic parameters of BRD7929 and BRD3316 were determined in CD-1 mice. BRD7929 and BRD3316 were formulated in 10% ethanol, 4% Tween, 86% saline for both intravenous and oral dosing. Pharmacokinetic parameters were estimated by non-compartmental model using WinNonlin 6.2. Pharmacokinetic parameters for BRD7929 and BRD3316 were estimated by a non-compartmental model using proprietary Eisai software. Pharmacokinetic parameters of BRD7539 and BRD9185 were determined in CD-1 mice. Compounds were formulated in 70% PEG300 and 30% (5% glucose in H O) at 0.5 mg ml−1 for oral dosing, and 5% DMSO, 10% cremophor, and 85% H O at 0.25 mg ml−1 for intravenous formulation. Pharmacokinetic parameters were estimated by non-compartmental model using WinNonlin 6.2. Pharmacokinetics of BRD7539 and BRD9185 were performed by WuXi AppTec. The protocol was approved by Eisai IACUC, 13-07, 13, 05, and 14-c-0027. Compounds were evaluated in vitro to determine their metabolic stability in incubations containing liver microsomes or hepatocytes of mouse and human. In the presence of NADPH, liver microsomes (0.2 mg ml−1) from mouse (CD-1) and human were incubated with compounds (0.5 and 5 μM) for 0, 10 and 90 min. The depletion of compounds in the incubation mixtures, determined using liquid chromatography tandem mass spectromety LC–MS/MS, was used to estimate K and V values and determine half-lives for both mouse and human microsomes. Compounds were evaluated in vitro for the potential inhibition of human cytochrome P450 (CYP) isoforms using human liver microsomes. Two concentrations (1 and 10 μM) of compound were incubated with pooled liver microsomes (0.2 mg ml−1) and a cocktail mixture of probe substrates for selective CYP isoform. The selective activities tested were CYP1A2-mediated phenacetin O-demethylation, CYP2C8-mediated rosiglitazone para-hydroxylation, CYP2C9-mediated tolbutamide 4′-hydroxylation, CYP2C19-mediated (S)-mephenytoin 4′-hydroxylation, CYP2D6-mediated (±)-bufuralol 1′-hydroxylation and, CYP3A4/5-mediated midazolam 1′-hydroxylation. The positive controls tested were α-naphthoflavone for CYP1A2, montelukast for CYP2C8, sulfaphenazole for CYP2C9, tranylcypromine for CYP2C19, quinidine for CYP2D6, and ketoconazole for CYP3A4/5. The samples were analysed by LC–MS/MS. IC values were estimated using nonlinear regression. The time-dependent inactivation potential of compounds were assessed in human liver microsomes for CYP2C9, CYP2D6, and CYP3A4/5 by determining K and k values when appropriate. Two concentrations (6 and 30 μM) of compound were incubated in primary reaction mixtures containing phosphate buffer and 0.2 mg ml−1 human liver microsomes for 0, 5, and 30 min in a 37 °C water bath. The reactions were initiated by the addition of NADPH. Phosphate buffer was substituted for NADPH solution for control. At the respective times, 25 μl of primary incubation was diluted tenfold into pre-incubated secondary incubation mixture containing each CYP-selective probe substrate in order to assess residual activity. The second incubation time was 10 min. The probe substrates used for CYP1A, 2C9, CYP2C19, CYP2D6, and CYP3A4 were phenacetin (50 μM), tolbutamide (500 μM), (S)-mephenytoin (20 μM), bufuralol (50 μM), and midazolam (30 μM), respectively. The CYP time- dependent inhibitors used were furafyllin, tienilic acid, ticlopidine, paroxetin and troleandomycin for CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, respectively, at two concentrations. The samples were analysed by LC–MS/MS.

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