2. Academic Validation
  3. Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9

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

  • Bioorg Med Chem. 2015 Oct 1;23(19):6280-96. doi: 10.1016/j.bmc.2015.08.035.
Louisa J Phillipson 1,  David H Segal 1,  Tracy L Nero 2,  Michael W Parker 3,  Soo San Wan 1,  Melanie de Silva 1,  Mark A Guthridge 4,  Andrew H Wei 5,  Christopher J Burns 6
Affiliations

Affiliations

  • 1 ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, 1G Royal Parade, VIC 3052, Australia.
  • 2 ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, 41 Victoria Pde, Fitzroy, VIC 3065, Australia.
  • 3 ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC 3010, Australia.
  • 4 Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, 89 Commercial Rd, Melbourne, VIC 3004, Australia.
  • 5 Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, 89 Commercial Rd, Melbourne, VIC 3004, Australia; Department of Clinical Haematology, The Alfred Hospital, Commercial Rd, Melbourne, VIC 3004, Australia.
  • 6 ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, 1G Royal Parade, VIC 3052, Australia; School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Rd, VIC 3010, Australia. Electronic address: burns@wehi.edu.au.
PMID: 26349627 DOI: 10.1016/j.bmc.2015.08.035
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.

Keywords

CDK7; CDK9 selectivity; FLT3; Molecular modelling; PI3Kα; Pyrazolo[1,5-a]pyrimidine.

Figures