Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1 |
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| Institution: | 1. Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States;2. Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States;3. Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States;4. Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States;5. Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom;1. Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary;2. Department of Inorganic and Analytical Chemistry, University of Debrecen, POB 21, H-4010 Debrecen, Hungary;1. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;1. Sri Sathya Sai Institute of Higher Learning, Prashanthi Nilayam, A.P, 51513, India;2. Department of Biotechnology, School of Biosciences and Technology, VIT University, Vellore, 632014, India;3. Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, 632014, India;1. Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India;2. Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India;3. Analytical Chemistry-Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India;1. Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK;2. Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;3. Discovery Biology, Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany |
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| Abstract: | Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1. |
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| Keywords: | ChK1 Checkpoint Structure-based design Diazacarbazole GNE-783 |
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