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.
- 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: [email protected].
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.