jm9b00189_si_001.pdf (5.47 MB)
3,5,7-Substituted Pyrazolo[4,3‑d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models
journal contribution
posted on 2019-04-03, 00:00 authored by Radek Jorda, Libor Havlíček, Antonín Šturc, Diana Tušková, Lenka Daumová, Mahmudul Alam, Jana Škerlová, Michaela Nekardová, Miroslav Peřina, Tomáš Pospíšil, Jitka Široká, Lubor Urbánek, Petr Pachl, Pavlína Řezáčová, Miroslav Strnad, Pavel Klener, Vladimír KryštofCyclin-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.
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PARPBCL 2-targeting venetoclax4.35pyrimidine Inhibitorsantiproliferative activityfindings support60 cancer cell linescyclin-dependent kinasescombinatorial treatmentnon-Hodgkin lymphoma cell linesLymphoma Models Cyclin-dependent kinasesXIAPCultured lymphoma cell linesCDK inhibitorsCDK substratesposition 5Cyclin-Dependent Kinases5- sulfanyl groupcombination therapycell line xenograftpatient-derived xenograft mouse modelsMCL
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