Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F23%3A00571975" target="_blank" >RIV/61389030:_____/23:00571975 - isvavai.cz</a>

Alternative codes found

RIV/61388963:_____/23:00571975 RIV/61989592:15310/23:73619592

Result on the web

<a href="https://doi.org/10.1016/j.biopha.2023.114492" target="_blank" >https://doi.org/10.1016/j.biopha.2023.114492</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2023.114492" target="_blank" >10.1016/j.biopha.2023.114492</a>

Result language

angličtina

Original language name

Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7

Original language description

Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 Å resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30107 - Medicinal chemistry

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

Publication year

2023

Confidentiality

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

Name of the periodical

Biomedicine & Pharmacotherapy

ISSN

0753-3322

e-ISSN

1950-6007

Volume of the periodical

161

Issue of the periodical within the volume

MAY

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

9

Pages from-to

114492

UT code for WoS article

000955895000001

EID of the result in the Scopus database

2-s2.0-85150164521