Cellumen Inc.

Pittsburgh, PA, United States

Cellumen Inc.

Pittsburgh, PA, United States

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Schmidt A.,Merck And Co. | Kimmel D.B.,Merck And Co. | Bai C.,Merck And Co. | Bai C.,Pharmaron Inc. | And 34 more authors.
Journal of Biological Chemistry | Year: 2010

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


News Article | December 15, 2016
Site: www.businesswire.com

HAMBURG, Germany--(BUSINESS WIRE)--Evotec AG (Frankfurt Stock Exchange: EVT, TecDAX, ISIN: DE0005664809) today announced the successful closing of the acquisition of 100% shares in Cyprotex PLC ("Cyprotex", AIM: CRX-GB), a specialist pre-clinical contract research organisation in ADME-Tox and DMPK headquartered in the UK. The proposed acquisition was announced in detail on 26 October 2016. Following a scheme of arrangement regulated by the UK takeover code, all shares of Cyprotex have been acquired by and transferred to Evotec AG effective 14 December 2016 and the shares will this morning be cancelled from AIM. Evotec is paying £ 55.7 m (EUR 66.3 m; at an assumed £/EUR exchange rate of 1.19) in cash for the acquisition of all 26.1 million issued and to be issued Cyprotex shares and the funding of company debt mainly in the context of loan notes. The offer of 1.60 £ per Cyprotex share reflects a 9.4% premium to the VWAP of the past 30 trading days at AIM prior to the offer on 26 October 2016. MCF Corporate Finance, led by Ian Henderson, acted as Evotec's exclusive financial adviser throughout the acquisition process. Cyprotex, headquartered in the UK, was founded in 1999 and is publicly traded on AIM (CRX). The company currently has 136 employees working from sites at Macclesfield and Alderley Park, both of which are located near Manchester in the UK, and at Watertown, MA, and Kalamazoo, MI, in the USA. Cyprotex will continue to operate and serve its loyal client base in all currently existing segments under its brand name "Cyprotex" whilst employees and capabilities will be integrated into Evotec's global drug discovery group, thereby leveraging both companies' extensive partner networks and identifying further commercial synergies. Dr Mario Polywka, Chief Operating Officer of Evotec, commented: "We are pleased the acquisition has closed and we can now approach the exciting phase of welcoming Cyprotex' employees and clients to our global drug discovery services platform. The addition of the market's most industrialised ADME-Tox platform and proven expertise in in vitro ADME screening, mechanistic and high-content toxicology screening and predictive modelling to our offering substantially improves our ability to provide our alliance partners with access to the most comprehensive drug discovery platform. Cyprotex' proven technology platform and its expert and dedicated employees perfectly augment Evotec's business strategy and offering." Dr Werner Lanthaler, Chief Executive Officer of Evotec, added: "The highest quality and completeness of our drug discovery platform is key to improve the efficiency in the process for our partners. With Cyprotex we make here an important next step. We warmly welcome the Cyprotex employees to the Evotec Group and look forward to working with them." Evotec confirms its liquidity guidance for 2016. The Company expects liquidity to be at a similar level to the prior year, excluding any potential cash outflow for M&A or similar transactions. Based on current estimates, it is expected that the Cyprotex business will add approx. EUR 18-20 m in revenues in 2017 and will be accretive to Evotec's 2017 EBITDA. Cyprotex is listed on the AIM market of the London Stock Exchange (CRX). It has sites at Macclesfield and Alderley Park, both of which are near Manchester in the UK, and at Watertown, MA and Kalamazoo, MI in the US. The Company was established in 1999 and works with more than 1500 partners within the pharmaceutical and biotech industry, cosmetics and personal care industry and the chemical industry. Cyprotex acquired Apredica and the assets of Cellumen Inc. in August 2010 and the combined business provides support for a wide range of experimental and computational ADME-Tox and PK services. The acquisition of the assets and business of CeeTox in January 2014 has enabled Cyprotex to expand its range of services to target the personal care, cosmetics and chemical industries. In 2015, Cyprotex launched its new bioscience division to expand its capabilities into phenotypic and target based screening. The Company's core capabilities include high quality in vitro ADME services, mechanistic toxicology and high content toxicology screening services, including its proprietary CellCiphr(R) toxicity prediction technology, bioscience services, predictive modelling solutions including Cloe(R) PK, chemPK(TM), chemTarget, chemTox and DDI-Fusion and a range of skin, ocular and endocrine disruption services. For more information, please visit www.cyprotex.com. Evotec is a drug discovery alliance and development partnership company focused on rapidly progressing innovative product approaches with leading pharmaceutical and biotechnology companies, academics, patient advocacy groups and venture capitalists. We operate worldwide providing the highest quality stand-alone and integrated drug discovery solutions, covering all activities from target-to-clinic to meet the industry's need for innovation and efficiency in drug discovery (EVT Execute). The Company has established a unique position by assembling top-class scientific experts and integrating state-of-the-art technologies as well as substantial experience and expertise in key therapeutic areas including neuroscience, diabetes and complications of diabetes, pain and inflammation, oncology and infectious diseases. On this basis, Evotec has built a broad and deep pipeline of more than 70 partnered product opportunities at clinical, pre-clinical and discovery stages (EVT Innovate). Evotec has established multiple long-term discovery alliances with partners including Bayer, CHDI, Sanofi or UCB and development partnerships with e.g. Janssen Pharmaceuticals in the field of Alzheimer's disease, with Sanofi in the field of diabetes and with Pfizer in the field of tissue fibrosis. For additional information please go to www.evotec.com. MCF Corporate Finance ("MCF") is a leading independent and international corporate finance advisory firm with offices in Hamburg, Helsinki, London and Stockholm. The company was established in 1987 and is run as an independent partnership. MCF specialises in cross-border and domestic M&A transactions in the European markets. Its multinational team consists of more than 40 corporate finance specialists with extensive experience in industry, banking, finance, accounting and law. MCF has previously advised Evotec on several transactions in both Germany and the UK. For further information, please go to www.mcfcorpfin.com/en. Information set forth in this press release contains forward-looking statements, which involve a number of risks and uncertainties. The forward-looking statements contained herein represent the judgement of Evotec as of the date of this press release. Such forward-looking statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.


News Article | December 15, 2016
Site: www.businesswire.com

HAMBURG, Deutschland--(BUSINESS WIRE)--Evotec AG (Frankfurter Wertpapierbörse: EVT, TecDAX, ISIN: DE0005664809) gab heute den erfolgreichen Abschluss der Akquisition von 100% aller Anteile an der Cyprotex PLC ("Cyprotex", AIM: CRX-GB) bekannt. Cyprotex ist ein auf präklinische ADME-Tox- und DMPK-Leistungen spezialisiertes Auftragsforschungsunternehmen mit Hauptsitz in UK. Die beabsichtigte Akquisition wurde detailliert am 26. Oktober 2016 bekannt gegeben. Mittels eines detaillierten Übernahmeplans, des sogenannten Scheme of Arrangements, der durch den UK Takeover Code geregelt wird, wurden alle Anteile an der Cyprotex mit Wirkung zum 14. Dezember 2016 durch die Evotec AG erworben und transferiert. Im Verlauf des heutigen Morgens erfolgt ein Delisting der Cyprotex-Aktien von der AIM. Evotec entrichtet 55,7 Mio. £ (66,3 Mio. EUR bei einem angenommenen £/EUR-Kurs von 1,19) in bar für die Übernahme aller 26,1 Mio. ausgegebenen und noch auszugebenden Cyprotex-Aktien und die Übernahme der Verbindlichkeiten des Unternehmens, die hauptsächlich aus ausgegebenen Anleihen bestehen. Das Angebot von 1,60 £ pro Cyprotex-Aktie entspricht einem 9,4%-Aufschlag auf den VWAP (volumengewichteter Durchschnittskurs) der letzten 30 Handelstage an der AIM vor Unterbreitung des Angebots am 26. Oktober 2016. MCF Corporate Finance unter der Leitung von Ian Henderson fungierte während des Übernahmeprozesses als exklusiver Finanzberater von Evotec. Cyprotex hat seinen Hauptsitz in UK, wurde im Jahr 1999 gegründet und ist an der AIM (CRX) notiert. Das Unternehmen hat derzeit 136 Mitarbeiter, die an den Standorten Macclesfield and Alderley Park (beide in der Nähe von Manchester, UK) sowie Watertown, MA, und Kalamazoo, MI, in den USA beschäftigt sind. Cyprotex wird weiterhin seinen loyalen Kundenstamm in allen derzeitig bestehenden Segmenten unter der Marke Cyprotex bedienen. Die Mitarbeiter und Kapazitäten sowie Fähigkeiten werden gleichzeitig in Evotecs globale Wirkstoffforschungsplattform integriert, um die umfangreichen Partnernetzwerke beider Unternehmen wirksam einzusetzen und weitere kommerzielle Synergien zu identifizieren. Dr. Mario Polywka, Chief Operating Officer von Evotec, kommentierte: "Wir freuen uns sehr, dass die Übernahme nun abgeschlossen ist und wir in die nächste spannende Phase eintreten können, in der wir die Cyprotex-Mitarbeiter und -Kunden auf unserer globalen Wirkstoffforschungsplattform begrüßen dürfen. Die Akquisition dieser industrialisierten ADME-Tox-Plattform und nachgewiesener Expertise in in vitro-ADME-Screening, mechanistischem sowie High-Content Toxicology-Screening und Vorhersagemodellen bedeutet eine Stärkung unserer hochwertigen Wirkstoffforschungsplattform und Expertise in diesem Bereich und ermöglicht unseren Partnern Zugang zu einer äußerst umfangreichen Wirkstoffforschungsplattform. Die bewährte Technologieplattform von Cyprotex und die erfahrenen und engagierten Mitarbeiter stellen eine sehr gute Ergänzung unserer Strategie und unseres Angebots dar." Cyprotex ist im AIM-Segment der London Stock Exchange notiert (CRX). Das Unternehmen verfügt über Standorte in Macclesfield und Alderley Park, beide in der Nähe von Manchester, UK, sowie in Watertown, MA, und Kalamazoo, MI, in den USA. Cyprotex wurde im Jahr 1999 gegründet und arbeitet mit mehr als 1.500 Partnern aus der Pharma- und Biotechbranche, Kosmetik-, Personal Care- und Chemiebranche zusammen. Im Jahr 2010 hat Cyprotex Apredica und die Vermögenswerte von Cellumen Inc. erworben. Das daraus resultierende gemeinsame Geschäft bietet Unterstützung in einer Vielzahl von experimentellen und computerbasierten ADME-Tox- und PK-Leistungen an. Infolge der Übernahme von CeeTox im Januar 2014 konnte Cyprotex seine Bandbreite von Leistungen auf die Bereiche Personal Care, Kosmetik und Chemie ausweiten. Im Jahr 2015 erweiterte Cyprotex mit dem neuen Bioscience-Bereich seine Fähigkeiten in den Bereichen phänotypisches und targetbasiertes Screening. Zu den Kernkompetenzen des Unternehmens zählen hochwertige in vitro-ADME-Leistungen, mechanistische Toxikologie und High Content Toxicology Screening Services, darunter die proprietären Technologien CellCiphr(R) (toxicity prediction technology), Bioscience-Leistungen, Vorhersagemodelle wie Cloe(R) PK, chemPKTM, chemTarget, chemTox und DDI-Fusion, sowie eine Vielzahl von Leistungen in Bezug auf Haut-, okulare und endokrine Disruptoren. Weitere Informationen finden Sie unter www.cyprotex.com. Evotec ist ein Wirkstoffforschungs- und -entwicklungsunternehmen, das in Forschungsallianzen und Entwicklungspartnerschaften mit führenden Pharma- und Biotechnologieunternehmen, akademischen Einrichtungen, Patientenorganisationen und Risikokapitalgesellschaften innovative Ansätze zur Entwicklung neuer pharmazeutischer Produkte zügig vorantreibt. Wir sind weltweit tätig und bieten unseren Kunden qualitativ hochwertige, unabhängige und integrierte Lösungen im Bereich der Wirkstoffforschung an. Dabei decken wir alle Aktivitäten vom Target bis zur klinischen Entwicklung ab, um dem Bedarf der Branche an Innovation und Effizienz in der Wirkstoffforschung begegnen zu können (EVT Execute). Durch das Zusammenführen von erstklassigen Wissenschaftlern, modernsten Technologien sowie umfangreicher Erfahrung und Expertise in wichtigen Indikationsgebieten wie zum Beispiel Neurowissenschaften, Diabetes und Diabetesfolgeerkrankungen, Schmerz und Entzündungskrankheiten, Onkologie und Infektionskrankheiten ist Evotec heute einzigartig positioniert. Auf dieser Grundlage hat Evotec ihre Pipeline bestehend aus mehr als 70 verpartnerten Programmen in klinischen, präklinischen und Forschungsphasen aufgebaut (EVT Innovate). Evotec arbeitet in langjährigen Forschungsallianzen mit Partnern wie Bayer, CHDI, Sanofi oder UCB zusammen. Darüber hinaus verfügt das Unternehmen über Entwicklungspartnerschaften u. a. mit Janssen Pharmaceuticals im Bereich der Alzheimer'schen Erkrankung, mit Sanofi im Bereich Diabetes und mit Pfizer auf dem Gebiet Organfibrose. Weitere Informationen finden Sie auf unserer Homepage. www.evotec.com. MCF Corporate Finance ("MCF") ist eine führende unabhängige und international tätige Corporate Finance Beratung mit eigenen Standorten in Hamburg, Helsinki, London und Stockholm. MCF wurde 1987 gegründet und wird als unabhängige Partnerschaft geführt. MCF ist auf inländische und grenzüberschreitende M&A Transaktionen im europäischen Raum spezialisiert. Das multinationale Team von MCF besteht aus mehr als 40 Corporate Finance-Spezialisten mit umfangreicher Expertise in den Bereichen Industrie, Bank, Finanzen, Rechnungswesen und Recht. MCF hat Evotec bereits bei diversen Transaktionen sowohl in Deutschland als auch in UK beraten. Weitere Informationen finden Sie unter www.mcfcorpfin.com/en.


Dudgeon D.D.,University of Pittsburgh | Shinde S.,University of Pittsburgh | Yun Hua,University of Pittsburgh | Tong Ying Shun,University of Pittsburgh | And 6 more authors.
Journal of Biomolecular Screening | Year: 2010

In recent years, advances in structure-based drug design and the development of an impressive variety of high-throughput screening (HTS) assay formats have yielded an expanding list of protein-protein interaction inhibitors. Despite these advances, protein-protein interaction targets are still widely considered difficult to disrupt with small molecules. The authors present here the results from screening 220,017 compounds from the National Institute of Healths small-molecule library in a novel p53-hDM2 protein-protein interaction biosensor (PPIB) assay. The p53-hDM2 positional biosensor performed robustly and reproducibly throughout the high-content screening (HCS) campaign, and analysis of the multiparameter data from images of the 3 fluorescent channels enabled the authors to identify and eliminate compounds that were cytotoxic or fluorescent artifacts. The HCS campaign yielded 3 structurally related methylbenzo-naphthyridin-5-amine (MBNA) hits with IC50s between 30 and 50 μM in the p53-hDM2 PPIB. In HCT116 cells with wild-type (WT) p53, the MBNAs enhanced p53 protein levels, increased the expression of p53 target genes, caused a cell cycle arrest in G1, induced apoptosis, and inhibited cell proliferation with an IC50 ∼4 μM. The prototype disruptor of p53-hDM2 interactions Nutlin-3 was more potent than the MBNAs in the p53-hDM2 PPIB assay but produced equivalent biological results in HCT116 cells WT for p53. Unlike Nutlin-3, however, MBNAs also increased the percentage of apoptosis in p53 null cells and exhibited similar potencies for growth inhibition in isogenic cell lines null for p53 or p21. Neither the MBNAs nor Nutin-3 caused cell cycle arrest in p53 null HCT116 cells. Despite the relatively modest size of the screening library, the combination of a novel p53-hDM2 PPIB assay together with an automated imaging HCS platform and image analysis methods enabled the discovery of a novel chemotype series that disrupts p53-hDM2 interactions in cells. © 2010 Society for Laboratory Automation and Screening.


Johnston P.A.,University of Pittsburgh | Dudgeon D.D.,University of Pittsburgh | Shinde S.N.,University of Pittsburgh | Shun T.Y.,University of Pittsburgh | And 5 more authors.
Assay and Drug Development Technologies | Year: 2010

We present here the characterization and optimization of a novel imaging-based positional biosensor high-content screening (HCS) assay to identify disruptors of p53-hDM2 protein-protein interactions (PPIs). The chimeric proteins of the biosensor incorporated the N-terminal PPI domains of p53 and hDM2, protein targeting sequences (nuclear localization and nuclear export sequence), and fluorescent reporters, which when expressed in cells could be used to monitor p53-hDM2 PPIs through changes in the subcellular localization of the hDM2 component of the biosensor. Coinfection with the recombinant adenovirus biosensors was used to express the NH-terminal domains of p53 and hDM2, fused to green fluorescent protein and red fluorescent protein, respectively, in U-2 OS cells. We validated the p53-hDM2 PPI biosensor (PPIB) HCS assay with Nutlin-3, a compound that occupies the hydrophobic pocket on the surface of the N-terminus of hDM2 and blocks the binding interactions with the N-terminus of p53. Nutlin-3 disrupted the p53-hDM2 PPIB in a concentration-dependent manner and provided a robust, reproducible, and stable assay signal window that was compatible with HCS. The p53-hDM2 PPIB assay was readily implemented in HCS and we identified four (4) compounds in the 1,280-compound Library of Pharmacologically Active Compounds that activated the p53 signaling pathway and elicited biosensor signals that were clearly distinct from the responses of inactive compounds. Anthracycline (topoisomerase II inhibitors such as mitoxantrone and ellipticine) and camptothecin (topoisomerase I inhibitor) derivatives including topotecan induce DNA double strand breaks, which activate the p53 pathway through the ataxia telangiectasia mutated-checkpoint kinase 2 (ATM-CHK2) DNA damage response pathway. Although mitoxantrone, ellipticine, camptothecin, and topotecan all exhibited concentration-dependent disruption of the p53-hDM2 PPIB, they were much less potent than Nutlin-3. Further, their corresponding cellular images and quantitative HCS data did not completely match the Nutlin-3 phenotypic profile. © Copyright 2010, Mary Ann Liebert, Inc. 2010.


Giuliano K.A.,Cellumen Inc. | Gough A.H.,Cellumen Inc. | Lansing Taylor D.,Cellumen Inc. | Vernetti L.A.,Cellumen Inc. | Johnston P.A.,Cellumen Inc.
Journal of Biomolecular Screening | Year: 2010

The integration of high-content screening (HCS) readers with organ-specific cell models, panels of functional biomarkers, and advanced informatics is a powerful approach to identifying the toxic liabilities of compounds early in the development process and forms the basis of "early safety assessment." This cellular systems biology (CSB™) approach (CellCiphr® profile) has been used to integrate rodent and human cellular hepatic models with panels of functional biomarkers measured at multiple time points to profile both the potency and specificity of the cellular toxicological response. These profiles also provide initial insights on the mechanism of the toxic response. The authors describe here mechanistic assay profiles designed to further dissect the toxic mechanisms of action and elucidate subtle effects apparent in subpopulations of cells. They measured 8 key mechanisms of toxicity with multiple biomarker feature measurements made simultaneously in populations of living primary hepatocytes and HepG2 cells. Mining the cell population response from these mechanistic profiles revealed the concentration dependence and nature of the heterogeneity of the response, as well as relationships between the functional responses. These more detailed mechanistic profiles define differences in compound activities that are not apparent in the average population response. Because cells and tissues encounter wide ranges of drug doses in space and time, these mechanistic profiles build on the CellCiphr ® profile and better reflect the complexity of the response in vivo. © 2010 Society for Laboratory Automation and Screening.


PubMed | Cellumen Inc.
Type: Historical Article | Journal: Journal of biomolecular screening | Year: 2010

High-content screening (HCS) was introduced in 1997 based on light microscope imaging technologies to address the need for an automated platform that could analyze large numbers of individual cells with subcellular resolution using standard microplates. Molecular specificity based on fluorescence was a central element of the platform taking advantage of the growing list of reagent classes and the ability to multiplex. In addition, image analysis coupled to data management, data mining, and data visualization created a tool that focused on biological information and knowledge to begin exploring the functions of genes identified in the genomics revolution. This overview looks at the development of HCS, the evolution of the technologies, and the market up to the present day. In addition, the options for adopting uniform definitions is suggested along with a perspective on what advances are needed to continue building the value of HCS in biomedical research, drug discovery, and development and diagnostics.


PubMed | Cellumen Inc.
Type: Journal Article | Journal: Journal of biomolecular screening | Year: 2010

The integration of high-content screening (HCS) readers with organ-specific cell models, panels of functional biomarkers, and advanced informatics is a powerful approach to identifying the toxic liabilities of compounds early in the development process and forms the basis of early safety assessment. This cellular systems biology (CSB) approach (CellCiphr profile) has been used to integrate rodent and human cellular hepatic models with panels of functional biomarkers measured at multiple time points to profile both the potency and specificity of the cellular toxicological response. These profiles also provide initial insights on the mechanism of the toxic response. The authors describe here mechanistic assay profiles designed to further dissect the toxic mechanisms of action and elucidate subtle effects apparent in subpopulations of cells. They measured 8 key mechanisms of toxicity with multiple biomarker feature measurements made simultaneously in populations of living primary hepatocytes and HepG2 cells. Mining the cell population response from these mechanistic profiles revealed the concentration dependence and nature of the heterogeneity of the response, as well as relationships between the functional responses. These more detailed mechanistic profiles define differences in compound activities that are not apparent in the average population response. Because cells and tissues encounter wide ranges of drug doses in space and time, these mechanistic profiles build on the CellCiphr profile and better reflect the complexity of the response in vivo.


PubMed | Cellumen Inc.
Type: Journal Article | Journal: Drug discovery today. Technologies | Year: 2014

High content screening (HCS) has emerged as an important platform technology for early drug discovery from target identification through in vitro ADME/Tox. The focus is now on implementing multiplexed assays, developing and using advanced reagents and developing and harnessing more sophisticated informatics tools. Multiplexed HCS assays have the potential to dramatically improve the early drug discovery process by creating systems cell biology profiles on the activities of compounds. It is predicted that multiplexed HCS assays will accelerate the overall workflow and produce deeper functional knowledge, thereby permitting better decisions on what compounds to pursue.:

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