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Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9
journal contribution
posted on 2015-10-01, 00:00 authored by Louisa J Phillipson, David H Segal, Tracy L Nero, Michael W Parker, Soo San Wan, Melanie de Silva, Mark GuthridgeMark Guthridge, Andrew H Wei, Christopher J BurnsThe serine–threonine kinase CDK9 is a target of emerging interest for the development of anti-cancer drugs. There are multiple lines of evidence linking CDK9 activity to cancer, including the essential role this kinase plays in transcriptional regulation through phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Indeed, inhibition of CDK9 has been shown to result in a reduction of short-lived proteins such as the pro-survival protein Mcl-1 in malignant cells leading to the induction of apoptosis. In this work we report our initial studies towards the discovery of selective CDK9 inhibitors, starting from the known multi-kinase inhibitor PIK-75 which possesses potent CDK9 activity. Our series is based on a pyrazolo[1,5-a]pyrimidine nucleus and, importantly, the resultant lead compound 18b is devoid of the structural liabilities present in PIK-75 and possesses greater selectivity.
History
Journal
Bioorganic & medicinal chemistryVolume
23Issue
19Pagination
6280 - 6296Publisher
ElsevierLocation
Amsterdam, The NetherlandsPublisher DOI
ISSN
0968-0896Language
engPublication classification
C1 Refereed article in a scholarly journalUsage metrics
Keywords
Science & TechnologyLife Sciences & BiomedicinePhysical SciencesBiochemistry & Molecular BiologyChemistry, MedicinalChemistry, OrganicPharmacology & PharmacyChemistryPyrazolo[1,5-a] pyrimidineCDK9 selectivityCDK7PI3K alphaFLT3Molecular modellingACUTE MYELOID-LEUKEMIAPI3-KINASE P110-ALPHA INHIBITORSCHRONIC LYMPHOCYTIC-LEUKEMIADEPENDENT KINASE INHIBITORSBIOLOGICAL EVALUATIONP-TEFBDRUG TARGETPHASE-IMCL-1FLAVOPIRIDOLPI3KαPyrazolo[1,5-a]pyrimidineOrganic Chemistry
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