Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9
Publication Year 2015, Volume 23, Issue #19, Page 6280-96
Journal Title
Bioorg Med Chem
Publication Type
Journal Article
The 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.
WEHI Research Division(s)
Chemical Biology
PubMed ID
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Creation Date: 2015-09-24 02:12:27
Last Modified: 2015-10-23 12:11:32
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