Deakin University
Browse

File(s) under permanent embargo

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 Burns
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.

History

Journal

Bioorganic & medicinal chemistry

Volume

23

Pagination

6280-6296

Location

Amsterdam, The Netherlands

ISSN

0968-0896

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Issue

19

Publisher

Elsevier