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3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models
R. Jorda, L. Havlíček, A. Šturc, D. Tušková, L. Daumová, M. Alam, J. Škerlová, M. Nekardová, M. Peřina, T. Pospíšil, J. Široká, L. Urbánek, P. Pachl, P. Řezáčová, M. Strnad, P. Klener, V. Kryštof,
Journal of medicinal chemistry.
2019 ;
62 (9) :
4606-4623.
[pub] 20190417
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc20023949
- MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické farmakologie MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- inhibitory proteinkinas chemická syntéza farmakologie terapeutické užití MeSH
- lidé MeSH
- lymfom farmakoterapie MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza farmakologie terapeutické užití MeSH
- pyrazoly chemická syntéza farmakologie terapeutické užití MeSH
- pyrimidiny chemická syntéza farmakologie terapeutické užití MeSH
- sulfonamidy farmakologie MeSH
- synergismus léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Citace poskytuje Crossref.org
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