2. Academic Validation
  3. 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)

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)

  • Bioorg Med Chem. 2016 Feb 15;24(4):521-44. doi: 10.1016/j.bmc.2015.11.045.
M V Ramana Reddy 1,  Balireddy Akula 2,  Shashidhar Jatiani 3,  Rodrigo Vasquez-Del Carpio 3,  Vinay K Billa 3,  Muralidhar R Mallireddigari 2,  Stephen C Cosenza 3,  D R C Venkata Subbaiah 3,  E Vijaya Bharathi 3,  Venkat R Pallela 2,  Poornima Ramkumar 3,  Rinku Jain 4,  Aneel K Aggarwal 4,  E Premkumar Reddy 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States.
  • 3 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
  • 4 Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
  • 5 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.
PMID: 26762835 DOI: 10.1016/j.bmc.2015.11.045
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.

Keywords

Apoptosis; Cytotoxicity; Kinase inhibitor; PLK.

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