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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)6280 - 6296
Number of pages17
JournalBioorganic & Medicinal Chemistry
Volume23
Issue number19 (Art. No: 12539)
DOIs
Publication statusPublished - 2015

Cite this

Phillipson, L. J., Segal, D., Nero, T. L., Parker, M. W., Wan, S. S., de Silva, M., ... Burns, C. J. (2015). Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9. Bioorganic & Medicinal Chemistry, 23(19 (Art. No: 12539)), 6280 - 6296. https://doi.org/10.1016/j.bmc.2015.08.035
Phillipson, Louisa J ; Segal, David ; Nero, Tracy L ; Parker, Michael William ; Wan, Soo San ; de Silva, Melanie ; Guthridge, Mark Andrew ; Wei, Andrew ; Burns, Christopher J. / Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9. In: Bioorganic & Medicinal Chemistry. 2015 ; Vol. 23, No. 19 (Art. No: 12539). pp. 6280 - 6296.
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title = "Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9",
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.",
author = "Phillipson, {Louisa J} and David Segal and Nero, {Tracy L} and Parker, {Michael William} and Wan, {Soo San} and {de Silva}, Melanie and Guthridge, {Mark Andrew} and Andrew Wei and Burns, {Christopher J}",
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Phillipson, LJ, Segal, D, Nero, TL, Parker, MW, Wan, SS, de Silva, M, Guthridge, MA, Wei, A & Burns, CJ 2015, 'Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9' Bioorganic & Medicinal Chemistry, vol. 23, no. 19 (Art. No: 12539), pp. 6280 - 6296. https://doi.org/10.1016/j.bmc.2015.08.035

Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9. / Phillipson, Louisa J; Segal, David; Nero, Tracy L; Parker, Michael William; Wan, Soo San; de Silva, Melanie; Guthridge, Mark Andrew; Wei, Andrew; Burns, Christopher J.

In: Bioorganic & Medicinal Chemistry, Vol. 23, No. 19 (Art. No: 12539), 2015, p. 6280 - 6296.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Phillipson, Louisa J

AU - Segal, David

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AB - 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.

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Phillipson LJ, Segal D, Nero TL, Parker MW, Wan SS, de Silva M et al. Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9. Bioorganic & Medicinal Chemistry. 2015;23(19 (Art. No: 12539)):6280 - 6296. https://doi.org/10.1016/j.bmc.2015.08.035