Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9

Author(s): Phillipson, LJ; Segal, DH; Nero, TL; Parker, MW; Wan, SS; de Silva, M; Guthridge, MA; Wei, AH; Burns, CJ;
Details: Publication Year 2015,Volume 23,Issue #19,Page 6280-96
Journal Title: Bioorg Med Chem
Publication Type: Journal Article
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.
Publisher: Elsevier
Research Division(s): Chemical Biology
PubMed ID: 26349627
Publisher's Version: https://doi.org/10.1016/j.bmc.2015.08.035
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-09-24 02:12:27

Last Modified: 2015-10-23 12:11:32