PMID- 26762835 OWN - NLM STAT- MEDLINE DCOM- 20161014 LR - 20240325 IS - 1464-3391 (Electronic) IS - 0968-0896 (Print) IS - 0968-0896 (Linking) VI - 24 IP - 4 DP - 2016 Feb 15 TI - 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). PG - 521-44 LID - S0968-0896(15)30168-1 [pii] LID - 10.1016/j.bmc.2015.11.045 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Reddy, M V Ramana AU - Reddy MV AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. Electronic address: r.reddy@mssm.edu. FAU - Akula, Balireddy AU - Akula B AD - Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States. FAU - Jatiani, Shashidhar AU - Jatiani S AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Vasquez-Del Carpio, Rodrigo AU - Vasquez-Del Carpio R AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Billa, Vinay K AU - Billa VK AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Mallireddigari, Muralidhar R AU - Mallireddigari MR AD - Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States. FAU - Cosenza, Stephen C AU - Cosenza SC AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Venkata Subbaiah, D R C AU - Venkata Subbaiah DR AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Bharathi, E Vijaya AU - Bharathi EV AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Pallela, Venkat R AU - Pallela VR AD - Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States. FAU - Ramkumar, Poornima AU - Ramkumar P AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Jain, Rinku AU - Jain R AD - Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Aggarwal, Aneel K AU - Aggarwal AK AD - Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. FAU - Reddy, E Premkumar AU - Reddy EP AD - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States. Electronic address: ep.reddy@mssm.edu. LA - eng GR - R01 CA158209/CA/NCI NIH HHS/United States GR - 1R01 CA158209/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151201 PL - England TA - Bioorg Med Chem JT - Bioorganic & medicinal chemistry JID - 9413298 RN - 0 (2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido(2,3-d)pyrimidin-7(8H)-one) RN - 0 (Indoles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidinones) RN - EC 2.7.11.- (PLK2 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Dose-Response Relationship, Drug MH - *Drug Discovery MH - Humans MH - Indoles/chemical synthesis/chemistry/*pharmacology MH - Molecular Structure MH - Protein Kinase Inhibitors/chemical synthesis/chemistry/*pharmacology MH - Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Pyrimidinones/chemical synthesis/chemistry/*pharmacology MH - Structure-Activity Relationship PMC - PMC5947326 MID - NIHMS964488 OTO - NOTNLM OT - Apoptosis OT - Cytotoxicity OT - Kinase inhibitor OT - PLK EDAT- 2016/01/15 06:00 MHDA- 2016/10/16 06:00 PMCR- 2018/05/11 CRDT- 2016/01/15 06:00 PHST- 2015/08/28 00:00 [received] PHST- 2015/11/20 00:00 [revised] PHST- 2015/11/29 00:00 [accepted] PHST- 2016/01/15 06:00 [entrez] PHST- 2016/01/15 06:00 [pubmed] PHST- 2016/10/16 06:00 [medline] PHST- 2018/05/11 00:00 [pmc-release] AID - S0968-0896(15)30168-1 [pii] AID - 10.1016/j.bmc.2015.11.045 [doi] PST - ppublish SO - Bioorg Med Chem. 2016 Feb 15;24(4):521-44. doi: 10.1016/j.bmc.2015.11.045. Epub 2015 Dec 1.