Journal article

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

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

Bioorganic & Medicinal Chemistry | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2015


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 act..

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Awarded by Australian National Health and Medical Research Council

Funding Acknowledgements

This work is supported by scholarships, fellowships and grants from the Australian National Health and Medical Research Council (Research Fellowship to M.W.P.; Independent Research Institutes Infrastructure Support Scheme Grants 9000220 and 9000225), Victorian State Government Operational Infrastructure Support (OIS) Grants, Australian Cancer Research Foundation, and Dyson Bequest funding (Dunn Fellowship to C.J.B.). We thank Prof. D.C.S. Huang for helpful advice and discussion. Ms. Dana Buczek is acknowledged for analytical support.