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

Bioorganic & Medicinal Chemistry
Louisa J PhillipsonChristopher J Burns

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.

References

Mar 10, 2010·Current Drug Targets·Vladimír Krystof, Stjepan Uldrijan
Jul 26, 2012·Blood Cancer Journal·S KasperT Fischer
Aug 7, 2012·Bioorganic & Medicinal Chemistry Letters·Ian BruceLewis Whitehead
Nov 13, 2012·Nucleic Acids Research·Frederik Otzen BaggerBo T Porse
Apr 15, 2014·Cell Cycle·Jianyou GuTahir H Tahirov

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Citations

May 14, 2016·Journal of Medicinal Chemistry·Yogesh A SonawaneAmarnath Natarajan
May 31, 2018·Future Medicinal Chemistry·Amy B HeptinstallIan R Hardcastle
Jul 25, 2020·European Journal of Medicinal Chemistry·Brilliant N MarakVed Prakash Singh
Dec 17, 2016·The Journal of Organic Chemistry·Juan-Carlos CastilloJaime Portilla
Aug 27, 2021·European Journal of Medicinal Chemistry·Vivek AsatiG D Gupta

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