Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2) |
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| Affiliation: | 1. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States;2. Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States;3. Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States;1. Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA;2. Platform Sciences and Technology, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA;1. The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, 3052, Australia;2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3052, Australia;3. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria, 3000, Australia;4. The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Parkville, Victoria, 3000, Australia;5. Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Victoria, 3004, Australia;1. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;2. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA;3. Eurofins DiscoverX, 42501 Albrae Street, Fremont, CA 94538, USA;4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;1. College of Life Sciences, Beijing Normal University, Beijing 100875, China;2. National Institute of Biological Sciences (NIBS), Beijing 102206, China;3. Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China |
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| Abstract: | Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao. |
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| Keywords: | PLK Kinase inhibitor Apoptosis Cytotoxicity |
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