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3,5,7-Substituted Pyrazolo[4,3‑<i>d</i>]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models

By Radek Jorda (1569763), Libor Havlíček (2204824), Antonín Šturc (1797040), Diana Tušková (6597008), Lenka Daumová (6597011), Mahmudul Alam (784446), Jana Škerlová (6597014), Michaela Nekardová (6597017), Miroslav Peřina (6597020), Tomáš Pospíšil (4216498), Jitka Široká (2925594), Lubor Urbánek (6597023), Petr Pachl (2209759), Pavlína Řezáčová (1265025), Miroslav Strnad (157788), Pavel Klener (77335) and Vladimír Kryštof (1569754)

Abstract

Cyclin-dependent kinases are therapeutic targets frequently deregulated in various cancers. By convenient alkylation of the 5-sulfanyl group, we synthesized 3-isopropyl-7-[4-(2-pyridyl)­benzyl]­amino-1(2)<i>H</i>-pyrazolo­[4,3-<i>d</i>]­pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative <b>4.35</b> also displayed activities across more than 60 cancer cell lines. The kinase profiling confirmed high selectivity of <b>4.35</b> toward cyclin-dependent kinases (CDKs) 2, 5, and 9, and the cocrystal with CDK2/cyclin A2 revealed its binding in the active site. Cultured lymphoma cell lines treated with <b>4.35</b> showed dephosphorylation of CDK substrates, cleavage of PARP-1, downregulation of XIAP and MCL-1, and activation of caspases, which collectively confirmed ongoing apoptosis. Moreover, <b>4.35</b> demonstrated significant activity in various cell line xenograft and patient-derived xenograft mouse models in vivo both as a monotherapy and as a combination therapy with the BCL2-targeting venetoclax. These findings support further studies of combinatorial treatment based on CDK inhibitors

Topics: Biochemistry, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biotechnology, Evolutionary Biology, Cancer, Mental Health, Infectious Diseases, Virology, Computational Biology, Chemical Sciences not elsewhere classified, PARP, BCL 2-targeting venetoclax, 4.35, pyrimidine Inhibitors, antiproliferative activity, findings support, 60 cancer cell lines, cyclin-dependent kinases, combinatorial treatment, non-Hodgkin lymphoma cell lines, Lymphoma Models Cyclin-dependent kinases, XIAP, Cultured lymphoma cell lines, CDK inhibitors, CDK substrates, position 5, Cyclin-Dependent Kinases, 5- sulfanyl group, combination therapy, cell line xenograft, patient-derived xenograft mouse models, MCL
Year: 2019
DOI identifier: 10.1021/acs.jmedchem.9b00189.s001
OAI identifier: oai:figshare.com:article/8006159
Provided by: FigShare
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