Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged...

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Published in:Journal of medicinal chemistry 2023-12, Vol.66 (23), p.15629-15647
Main Authors: Freeman, David B., Hopkins, Tamara D., Mikochik, Peter J., Vacca, Joseph P., Gao, Hua, Naylor-Olsen, Adel, Rudra, Sonali, Li, Huixu, Pop, Marius S., Villagomez, Rosa A., Lee, Christina, Li, Heng, Zhou, Minyun, Saffran, Douglas C., Rioux, Nathalie, Hood, Tressa R., Day, Melinda A. L., McKeown, Michael R., Lin, Charles Y., Bischofberger, Norbert, Trotter, B. Wesley
Format: Article
Language:English
Subjects:
Adult
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Cell Cycle Checkpoints
Cell Line, Tumor
Cyclin-Dependent Kinase 9
Cyclin-Dependent Kinases
Disease Models, Animal
Drug Annotation
Humans
Mice
Neoplasms - drug therapy
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
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Summary:Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physico­chemical and pharmaco­kinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c01233