Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers
David B. Freeman, Tamara D. Hopkins, Peter Mikochik, Joseph P. Vacca, Hua Gao, Adel M. Naylor-Olsen, Sonali Rudra, Huixu Li, Marius S. Pop, Rosa Villagomez, Christina Lee, Heng Li, Minyun Zhou, Douglas C. Saffran, Nathalie Rioux, Tressa Hood, Melinda Day, Michael R. McKeown, Charles Y. Lin, Norbert Bischofberger, B. Wesley Trotter
Abstract
High Resolution Image Download MS PowerPoint Slide 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.