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

Louisa J Phillipson, David Segal, Tracy L Nero, Michael William Parker, Soo San Wan, Melanie de Silva, Mark Andrew Guthridge, Andrew Wei, Christopher J Burns

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12 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)6280 - 6296
Number of pages17
JournalBioorganic & Medicinal Chemistry
Issue number19 (Art. No: 12539)
Publication statusPublished - 2015

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