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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00562052" target="_blank" >RIV/61388963:_____/22:00562052 - isvavai.cz</a>

  • Alternative codes found

    RIV/61389030:_____/22:00562052 RIV/00216208:11110/22:10445238 RIV/61989592:15310/22:73616092 RIV/00064165:_____/22:10445238

  • Result on the web

    <a href="https://doi.org/10.1021/acs.jmedchem.1c02184" target="_blank" >https://doi.org/10.1021/acs.jmedchem.1c02184</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1021/acs.jmedchem.1c02184" target="_blank" >10.1021/acs.jmedchem.1c02184</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10401 - Organic chemistry

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2022

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Journal of Medicinal Chemistry

  • ISSN

    0022-2623

  • e-ISSN

    1520-4804

  • Volume of the periodical

    65

  • Issue of the periodical within the volume

    13

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    16

  • Pages from-to

    8881-8896

  • UT code for WoS article

    000821678600001

  • EID of the result in the Scopus database

    2-s2.0-85134433935