3,5,7-Substituted Pyrazolo[4,3- d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders

0562052 - ÚEB 2023 RIV US eng J - Článek v odborném periodiku
Jorda, R. - Havlíček, Libor - Peřina, M. - Vojáčková, V. - Pospíšil, T. - Djukic, Stefan - Škerlová, Jana - Grúz, J. - Renešová, N. - Klener, P. - Řezáčová, Pavlína - Strnad, Miroslav - Kryštof, V.
3,5,7-Substituted Pyrazolo[4,3- d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.
Journal of Medicinal Chemistry. Roč. 65, č. 13 (2022), s. 8881-8896. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA MŠMT(CZ) EF16_019/0000729; GA ČR(CZ) GA20-25308S
Institucionální podpora: RVO:61389030 ; RVO:61388963
Klíčová slova: Antineoplastic Agents * Cell Line * Cyclin-Dependent Kinases
Obor OECD: Organic chemistry
Impakt faktor: 7.3, rok: 2022
Způsob publikování: Omezený přístup
https://doi.org/10.1021/acs.jmedchem.1c02184

3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 Å resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation.
Trvalý link: https://hdl.handle.net/11104/0334472