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News Article | March 4, 2016
Site: cen.acs.org

The enzyme MTH1 is a hot cancer drug target. Spurred in part by a pair of 2014 Nature papers that reported MTH1 inhibitors can kill cancer cells (C&EN, April 7, 2014, page 9), more than 20 industry and academic groups have started programs to develop small molecules to shut down the enzyme. In those 2014 papers, the research teams—one led by Thomas Helleday of the Karolinska Institute and the other by Giulio Superti-Furga of CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences—showed that MTH1 inhibitors attack cancer cells by blocking a process that protects the cells from the effects of oxidative stress (Nature 2014, DOI: 10.1038/nature13181and 10.1038/nature13194). Cancer cells operate under oxidative stress, which can kill the cells by damaging their DNA bases. MTH1 prevents the incorporation of bases damaged by oxidation into the DNA replication process, permitting cancer cells to proliferate and thrive. However, new research suggests that blocking MTH1 may not be a deathblow to cancer cells and that the cancer-killing abilities of reported MTH1 inhibitors may not be due to shutting down the enzyme. At an American Association for Cancer Research conference last November and in a follow-up paper (Bioorg. Med. Chem. Lett. 2016, DOI: 10.1016/j.bmcl.2016.02.026), Alessia Petrocchi and coworkers at the University of Texas MD Anderson Cancer Center report a compound that potently inhibits MTH1 activity in cancer cells but doesn’t actually kill the cells. Jason G. Kettle and coworkers at Astra­Zeneca also identified small molecules that block MTH1’s enzymatic action but have limited or zero anticancer activity. When they do kill cancer cells, it’s through “off-target, nonspecific, and MTH1-independent effects on cell growth,” the researchers report (J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem.5b01760). Furthermore, the team showed that cancer cells remained viable after silencing the MTH1 gene using siRNA or CRISPR. MTH1 inhibitors still killed these cells, further supporting the conclusion that other mechanisms besides MTH1 inhibition are at play. Kettle notes that an additional unpublished study by a “leading U.K. organization also fails to validate the MTH1 mechanism.” The AstraZeneca group concludes that the enzyme’s role in cancer cells and the usefulness of inhibiting it remain uncertain. On the basis of the new findings, more careful study is now needed on MTH1’s role as a cancer drug target, says MTH1 specialist Yusaku Nakabeppu of Kyushu University. Chuan He, an expert on nucleic acid modifications at the University of Chicago, calls the siRNA knockdown and CRISPR knockout data “quite convincing” and agrees that “more work is required to assess the role of MTH1 in cancer cell survival.” But not all researchers in the field are ready to abandon MTH1 just yet. Oxidative stress expert Priyamvada Rai of the University of Miami Miller School of Medicine says, “Our independent research consistently supports MTH1 as a valid target in cancer cells that sustain oxidative stress.” Also, the anticancer abilities of molecules cannot always be investigated effectively with cell studies such as those used in the two new papers, says Jessica Martinsson, head of medicinal chemistry at Sweden’s Sprint Bioscience, which has worked on MTH1 inhibitors. Helleday and Superti-Furga still think MTH1 inhibition plays a key role in their compounds’ abilities to attack cancer. Superti-Furga wonders whether the discrepancies between the 2014 papers and the recent reports are due to intricacies in the regulation of the MTH1 pathway, which isn’t well understood. He adds that if MTH1 inhibitors do have effects in the absence of MTH1, then it will be important to find out what the additional targets are. Helleday points out that the new findings are reminiscent of recent developments on another cancer drug target, poly(ADP-ribose) polymerase (PARP). There isn’t a detailed understanding of how inhibiting the enzyme kills cancer cells, he says, but this hasn’t stopped a PARP inhibitor—AstraZeneca’s Lynparza (olaparib)—from being approved by the Food & Drug Administration for treatment of ovarian cancer and getting expedited review status for treatment of prostate cancer. “The underlying MTH1 biology is much more complex than PARP biology,” Helleday says, “so we cannot exclude as-yet-unknown interactions that could act synergistically to produce the impressive cell-killing effects we observe with our compounds. I am convinced that connecting scientists across the world using open innovation, we can solve this complex puzzle together, in time.”


Receive press releases from iHealthcareAnalyst, Inc.: By Email Global Fragment-Based Drug Discovery (FBDD) Market Analysis: Services, End Users, Growth Trends and Forecast to 2020, New Research by iHealthcareAnalyst, Inc. Fragment-Based Drug Discovery Market by Service Type (FBDD and HTS Comparative Analysis, Fragment Screening, Biophysical Techniques, NMR Spectroscopy, DSF Assay, Fluorescence Polarization, Isothermal Titration Calorimetry, X-Ray Crystallography, SPR, Bilayer Interferometry, Mass Spectrometry, Capillary Electrophoresis, Biochemical Assays, Non-Biophysical Techniques, Fragment Optimization), End Users (Academic and Research Institutes, Biopharmaceuticals, CROs) 2016-2020. Maryland Heights, MO, February 22, 2017 --( Browse Fragment-Based Drug Discovery Market by Service Type or Components (Comparative Analysis of FBDD and HTS, Fragment Screening, Biophysical Techniques, NMR Spectroscopy, DSF Assay, Fluorescence Polarization, Isothermal Titration Calorimetry, X-Ray Crystallography, SPR, Bilayer Interferometry, Mass Spectrometry, Capillary Electrophoresis, Biochemical Assays, Non-Biophysical Techniques, Fragment Optimization), and End Users (Academic and Research Institutes, Biopharmaceutical Companies, and CROs) 2016-2020 report at https://www.ihealthcareanalyst.com/report/fragment-based-drug-discovery-market/ Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity. The global fragment-based drug discovery market segmentation is based on service types or components (comparative analysis of FBDD and HTS, fragment screening, biophysical techniques, NMR spectroscopy, DSF assay, fluorescence polarization, isothermal titration calorimetry, X-ray crystallography, SPR, bilayer interferometry, mass spectrometry, capillary electrophoresis, biochemical assays, non-biophysical techniques, fragment optimization), and end users (academic and research institutes, biopharmaceutical companies, and CROs). The global fragment-based drug discovery market report provides market size (Revenue USD Million 2013 to 2020), market share, market trends and forecasts growth trends (CAGR%, 2016 to 2020). The global fragment-based drug discovery market research report is further segmented by geography into North America (U.S., Canada), Latin America (Brazil, Mexico, Rest of LA), Europe (U.K., Germany, France, Italy, Spain, Rest of EU), Asia Pacific (Japan, China, India, Rest of APAC), and Rest of the World. The global fragment-based drug discovery market report also provides the detailed market landscape, market drivers, restraints, opportunities), market attractiveness analysis and profiles of major competitors in the global market including company overview, financial snapshot, key products, technologies and services offered, and recent developments. Major players operating in the global fragment-based drug discovery market and included in this report are Astex Pharmaceuticals, Alveus Pharmaceuticals, Beactica AB, Charles River Laboratories International, Inc., Crown Bioscience, Inc., Emerald BioStructures, Evotec A.G., Kinetic Discovery, Proteros Fragments, Structure Based Design, Sygnature Discovery, and Sprint Bioscience AB. To request Table of Contents and Sample Pages of this report visit: https://www.ihealthcareanalyst.com/report/fragment-based-drug-discovery-market/ About Us iHealthcareAnalyst, Inc. is a global healthcare market research and consulting company providing market analysis, and competitive intelligence services to global clients. The company publishes syndicate, custom and consulting grade healthcare reports covering animal healthcare, biotechnology, clinical diagnostics, healthcare informatics, healthcare services, medical devices, medical equipment, and pharmaceuticals. In addition to multi-client studies, we offer creative consulting services and conduct proprietary single-client assignments targeted at client’s specific business objectives, information needs, time frame and budget. Please contact us to receive a proposal for a proprietary single-client study. Contact Us iHealthcareAnalyst, Inc. 2109, Mckelvey Hill Drive, Maryland Heights, MO 63043 United States Email: sales@ihealthcareanalyst.com Website: https://www.ihealthcareanalyst.com Maryland Heights, MO, February 22, 2017 --( PR.com )-- The global fragment-based drug discovery market is estimated to reach USD 650 Million in 2020, growing at a CAGR of 10.6% from 2016 to 2020. Increasing adoption of fragment-based screening programs by most of the major pharmaceutical companies, increasing availability of more assay options in research departments of most pharmaceutical and biotechnology companies for high hit rates of fragment-based screens are the major drivers of the global fragment-based drug discovery market, and are likely continue this trend during the forecast period.Browse Fragment-Based Drug Discovery Market by Service Type or Components (Comparative Analysis of FBDD and HTS, Fragment Screening, Biophysical Techniques, NMR Spectroscopy, DSF Assay, Fluorescence Polarization, Isothermal Titration Calorimetry, X-Ray Crystallography, SPR, Bilayer Interferometry, Mass Spectrometry, Capillary Electrophoresis, Biochemical Assays, Non-Biophysical Techniques, Fragment Optimization), and End Users (Academic and Research Institutes, Biopharmaceutical Companies, and CROs) 2016-2020 report at https://www.ihealthcareanalyst.com/report/fragment-based-drug-discovery-market/Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity.The global fragment-based drug discovery market segmentation is based on service types or components (comparative analysis of FBDD and HTS, fragment screening, biophysical techniques, NMR spectroscopy, DSF assay, fluorescence polarization, isothermal titration calorimetry, X-ray crystallography, SPR, bilayer interferometry, mass spectrometry, capillary electrophoresis, biochemical assays, non-biophysical techniques, fragment optimization), and end users (academic and research institutes, biopharmaceutical companies, and CROs).The global fragment-based drug discovery market report provides market size (Revenue USD Million 2013 to 2020), market share, market trends and forecasts growth trends (CAGR%, 2016 to 2020). The global fragment-based drug discovery market research report is further segmented by geography into North America (U.S., Canada), Latin America (Brazil, Mexico, Rest of LA), Europe (U.K., Germany, France, Italy, Spain, Rest of EU), Asia Pacific (Japan, China, India, Rest of APAC), and Rest of the World. The global fragment-based drug discovery market report also provides the detailed market landscape, market drivers, restraints, opportunities), market attractiveness analysis and profiles of major competitors in the global market including company overview, financial snapshot, key products, technologies and services offered, and recent developments.Major players operating in the global fragment-based drug discovery market and included in this report are Astex Pharmaceuticals, Alveus Pharmaceuticals, Beactica AB, Charles River Laboratories International, Inc., Crown Bioscience, Inc., Emerald BioStructures, Evotec A.G., Kinetic Discovery, Proteros Fragments, Structure Based Design, Sygnature Discovery, and Sprint Bioscience AB.To request Table of Contents and Sample Pages of this report visit: https://www.ihealthcareanalyst.com/report/fragment-based-drug-discovery-market/About UsiHealthcareAnalyst, Inc. is a global healthcare market research and consulting company providing market analysis, and competitive intelligence services to global clients. The company publishes syndicate, custom and consulting grade healthcare reports covering animal healthcare, biotechnology, clinical diagnostics, healthcare informatics, healthcare services, medical devices, medical equipment, and pharmaceuticals.In addition to multi-client studies, we offer creative consulting services and conduct proprietary single-client assignments targeted at client’s specific business objectives, information needs, time frame and budget. Please contact us to receive a proposal for a proprietary single-client study.Contact UsiHealthcareAnalyst, Inc.2109, Mckelvey Hill Drive,Maryland Heights, MO 63043United StatesEmail: sales@ihealthcareanalyst.comWebsite: https://www.ihealthcareanalyst.com Click here to view the list of recent Press Releases from iHealthcareAnalyst, Inc.


Tresaugues L.,Karolinska Institutet | Lundback T.,Karolinska Institutet | Welin M.,Karolinska Institutet | Flodin S.,Karolinska Institutet | And 6 more authors.
PLoS ONE | Year: 2015

Human NUDT16 is a member of the NUDIX hydrolase superfamily. After having been initially described as an mRNA decapping enzyme, recent studies conferred it a role as an "housecleaning" enzyme specialized in the removal of hazardous (deoxy)inosine diphosphate from the nucleotide pool. Here we present the crystal structure of human NUDT16 both in its apo-form and in complex with its product inosine monophosphate (IMP). NUDT16 appears as a dimer whose formation generates a positively charged trench to accommodate substrate-binding. Complementation of the structural data with detailed enzymatic and biophysical studies revealed the determinants of substrate recognition and particularly the importance of the substituents in position 2 and 6 on the purine ring. The affinity for the IMP product, harboring a carbonyl in position 6 on the base, compared to purine monophosphates lacking a H-bond acceptor in this position, implies a catalytic cycle whose rate is primarily regulated by the product-release step. Finally, we have also characterized a phenomenon of inhibition by the product of the reaction, IMP, which might exclude non-deleterious nucleotides from NUDT16-mediated hydrolysis regardless of their cellular concentration. Taken together, this study details structural and regulatory mechanisms explaining how substrates are selected for hydrolysis by human NUDT16. © 2015 Trésaugues et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Larsson A.,Nanyang Technological University | Jansson A.,Nanyang Technological University | Aberg A.,Karolinska Institutet | Aberg A.,Sprint Bioscience | And 2 more authors.
Current Opinion in Chemical Biology | Year: 2011

Fragment-based ligand discovery constitutes a useful strategy for the generation of high affinity ligands with suitable physico-chemical properties to serve as drug leads. There is an increasing number of generic biophysical screening strategies established with the potential for accelerating the generation of useful fragment hits. Crystal structures of these hits can subsequently be used as starting points for fragment evolution to high affinity ligands. Emerging understanding of the efficiency and operative aspects of hit generation and structural characterization in FBLD suggests that this method should be well suited for academic ligand development of chemical tools and experimental therapeutics. © 2011 Elsevier Ltd.


Viklund J.,Astrazeneca | Kolmodin K.,Astrazeneca | Nordvall G.,Astrazeneca | Swahn B.-M.,Astrazeneca | And 4 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [J. Med. Chem. 2013, 56, 4181-4205]. The affinity predictions are described in detail by Roos et al. [J. Chem. Inf. 2014, DOI: 10.1021/ci400374z]. © 2014 American Chemical Society.


Sprint Bioscience | Entity website

Visiting address Novum Hlsovgen 7, 8th floor Huddinge Postal address Novum 141 57 Huddinge Sweden Telephone +46 (0)8-411 44 55


Sprint Bioscience | Entity website

Visiting address Novum Hlsovgen 7, 8th floor Huddinge Postal address Novum 141 57 Huddinge Sweden Telephone +46 (0)8-411 44 55


Sprint Bioscience | Entity website

Visiting address Novum Hlsovgen 7, 8th floor Huddinge Postal address Novum 141 57 Huddinge Sweden Telephone +46 (0)8-411 44 55


Sprint Bioscience | Entity website

Sprint Bioscience starts a diabetes program 30 November, 2015 | Press releases Sprint Bioscience has signed a collaboration agreement with the Lundberg Laboratory for Diabetes Research at Gothenburg University in which Sprint Bioscience will develop drug candidates against a new target protein that is central to the development of type 2 diabetes. Sprint Bioscience has in fact already identified series of substances and a chemistry program is in place ...

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