Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9.
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.
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.
Louisa J
LJ
Phillipson
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.
David H
DH
Segal
ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, 41 Victoria Pde, Fitzroy, VIC 3065, Australia.
Tracy L
TL
Nero
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.
Michael W
MW
Parker
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.
Soo San
SS
Wan
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.
Melanie
M
de Silva
Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, 89 Commercial Rd, Melbourne, VIC 3004, Australia.
Mark A
MA
Guthridge
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.
Andrew H
AH
Wei
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.
Christopher J
CJ
Burns
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006835:Hydrazones; C549211:PIK 75; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D013449:Sulfonamides; C527752:pyrazolo(1,5-a)pyrimidine; D042863:Cyclin-Dependent Kinase 9
CDK7; CDK9 selectivity; FLT3; Molecular modelling; PI3Kα; Pyrazolo[1,5-a]pyrimidine