pik-75 and pyrazolo(1-5-a)pyrimidine

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.

Topics: Antineoplastic Agents; Binding Sites; Cell Line; Cell Survival; Cyclin-Dependent Kinase 9; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Hydrazones; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Pyrazoles; Pyrimidines; Recombinant Proteins; Structure-Activity Relationship; Sulfonamides