Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9.
Bioorg Med Chem
; 23(19): 6280-96, 2015 Oct 01.
Article
in En
| MEDLINE
| ID: mdl-26349627
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Pyrimidines
/
Cyclin-Dependent Kinase 9
/
Enzyme Inhibitors
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2015
Document type:
Article
Affiliation country:
Australia