title: 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).
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.
authors.affiliation: 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.
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.affiliation: Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States.
authors.forename: Balireddy
authors.initials: B
authors.lastname: Akula
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Shashidhar
authors.initials: S
authors.lastname: Jatiani
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Vasquez-Del Carpio
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Billa
authors.affiliation: Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States.
authors.forename: Muralidhar R
authors.initials: MR
authors.lastname: Mallireddigari
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: D R C
authors.initials: DR
authors.lastname: Venkata Subbaiah
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: E Vijaya
authors.initials: EV
authors.lastname: Bharathi
authors.affiliation: Department of Medicinal Chemistry, Onconova Therapeutics Inc., 375 Pheasant Run, Newtown, PA 18940-3423, United States.
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Pallela
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Poornima
authors.initials: P
authors.lastname: Ramkumar
authors.affiliation: Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Rinku
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., New York, NY 10029-6514, United States.
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
authors.affiliation: 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.
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000611505:2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Apoptosis; Cytotoxicity; Kinase inhibitor; PLK