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3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00505109" target="_blank" >RIV/61388963:_____/19:00505109 - isvavai.cz</a>

  • Alternative codes found

    RIV/61389030:_____/19:00505109 RIV/00216208:11110/19:10399499 RIV/61989592:15310/19:73598514 RIV/68378050:_____/19:00541528

  • Result on the web

    <a href="http://doi.org/10.1021/acs.jmedchem.9b00189" target="_blank" >http://doi.org/10.1021/acs.jmedchem.9b00189</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1021/acs.jmedchem.9b00189" target="_blank" >10.1021/acs.jmedchem.9b00189</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models

  • Original language description

    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.

  • 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

    30107 - Medicinal 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

    2019

  • 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

  • Volume of the periodical

    62

  • Issue of the periodical within the volume

    9

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    18

  • Pages from-to

    4606-4623

  • UT code for WoS article

    000467781700022

  • EID of the result in the Scopus database

    2-s2.0-85064988419