Title: Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9
Authors: Phillipson, LJ
Segal, DH
Nero, TL
Parker, MW
Wan, SS
de Silva, M
Guthridge, MA
Wei, AH
Burns, CJ
Issue Year: 2015
Abstract 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.
URI: https://publications.svi.edu.au/publications/1950
Other Identifiers doi: 10.1016/j.bmc.2015.08.035. Epub 2015 Aug 2
Publication type Article
Grant ID GNT1021645