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)
| Autor: | Shashidhar S. Jatiani, Balireddy Akula, E. Premkumar Reddy, Poornima Ramkumar, Rinku Jain, E. Vijaya Bharathi, Aneel K. Aggarwal, Stephen C. Cosenza, M. V. Ramana Reddy, Vinay K. Billa, Muralidhar R. Mallireddigari, D. R. C. Venkata Subbaiah, Rodrigo Vasquez-Del Carpio, Venkat R. Pallela |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Indoles Clinical Biochemistry Pharmaceutical Science Pyrimidinones Polo-like kinase Protein Serine-Threonine Kinases Biochemistry PLK1 Article Gene product Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Drug Discovery Humans ASK1 Protein Kinase Inhibitors Molecular Biology Mitosis Dose-Response Relationship Drug Molecular Structure Kinase Chemistry Organic Chemistry Wild type Biological activity Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 24:521-544 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2015.11.045 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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