Počet záznamů: 1  

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

  1. 1.
    0579081 - ÚMG 2024 RIV US eng J - Článek v odborném periodiku
    Jorda, R. - Havlíček, L. - Peřina, M. - Vojáčková, V. - Pospíšil, T. - Djukic, S. - Škerlová, Jana - Grúz, J. - Renešová, N. - Klener, P. - Řezáčová, P. - Strnad, M. - Kryštof, V.
    3,5,7-Substituted Pyrazolo[4,3-id/i]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
    Institucionální podpora: RVO:68378050
    Klíčová slova: roscovitine * expression * cell line
    Obor OECD: Biochemistry and molecular biology
    Impakt faktor: 7.3, rok: 2022
    Způsob publikování: Omezený přístup
    https://pubs.acs.org/doi/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 & ANGS. 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/11104/0347953

     
     
Počet záznamů: 1  

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