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

0505109 - ÚEB 2020 RIV US eng J - Journal Article
Jorda, Radek - Havlíček, Libor - Šturc, Antonín - Tušková, D. - Daumová, L. - Alam, M. - Škerlová, Jana - Nekardová, Michaela - Peřina, Miroslav - Pospíšil, Tomáš - Široká, Jitka - Urbánek, Lubor - Pachl, Petr - Řezáčová, Pavlína - Strnad, Miroslav - Klener, P. - Kryštof, Vladimír
3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models.
Journal of Medicinal Chemistry. Roč. 62, č. 9 (2019), s. 4606-4623. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GA17-14007S; GA ČR(CZ) GBP208/12/G016
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : BIOLOGICAL EVALUATION * CELL-CYCLE * ROSCOVITINE
OECD category: Hematology; Medicinal chemistry (UOCHB-X)
Impact factor: 6.205, year: 2019
Method of publishing: Limited access
http://doi.org/10.1021/acs.jmedchem.9b00189

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)H-pyrazolo[4,3-d]pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative 4.35 also displayed activities across more than 60 cancer cell lines. The kinase profiling confirmed high selectivity of 4.35 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 4.35 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, 4.35 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.
Permanent Link: http://hdl.handle.net/11104/0296627