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3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models
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SYSNO ASEP 0505109 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models Author(s) Jorda, Radek (UEB-Q) ORCID, RID
Havlíček, Libor (UEB-Q) RID, ORCID
Šturc, Antonín (UEB-Q)
Tušková, D. (CZ)
Daumová, L. (CZ)
Alam, M. (CZ)
Škerlová, Jana (UOCHB-X) ORCID
Nekardová, Michaela (UOCHB-X) RID
Peřina, Miroslav (UEB-Q)
Pospíšil, Tomáš (UEB-Q) ORCID
Široká, Jitka (UEB-Q) ORCID
Urbánek, Lubor (UEB-Q) RID
Pachl, Petr (UOCHB-X) RID, ORCID
Řezáčová, Pavlína (UOCHB-X) RID, ORCID
Strnad, Miroslav (UEB-Q) RID, ORCID
Klener, P. (CZ)
Kryštof, Vladimír (UEB-Q) RID, ORCIDNumber of authors 17 Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 62, č. 9 (2019), s. 4606-4623Number of pages 18 s. Language eng - English Country US - United States Keywords BIOLOGICAL EVALUATION ; CELL-CYCLE ; ROSCOVITINE Subject RIV FD - Oncology ; Hematology OECD category Hematology R&D Projects GA17-14007S GA ČR - Czech Science Foundation (CSF) GBP208/12/G016 GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UEB-Q - RVO:61389030 ; UOCHB-X - RVO:61388963 UT WOS 000467781700022 EID SCOPUS 85064988419 DOI 10.1021/acs.jmedchem.9b00189 Annotation 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. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2020 Electronic address http://doi.org/10.1021/acs.jmedchem.9b00189
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