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

doi:10.1016/j.bmc.2015.08.035

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. Epub 2015 Aug 28.

Authors

Louisa J Phillipson¹, David H Segal¹, Tracy L Nero², Michael W Parker³, Soo San Wan¹, Melanie de Silva¹, Mark A Guthridge⁴, Andrew H Wei⁵, Christopher J Burns⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Binding Sites
Cell Line
Cell Survival / drug effects
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / genetics
Cyclin-Dependent Kinase 9 / metabolism
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Hydrazones / chemistry
Hydrazones / metabolism
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Pyrazoles / chemistry*
Pyrazoles / metabolism
Pyrazoles / pharmacology
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Hydrazones
PIK 75
Pyrazoles
Pyrimidines
Recombinant Proteins
Sulfonamides
pyrazolo(1,5-a)pyrimidine
Cyclin-Dependent Kinase 9