1区 · 医学
Article
作者: Saffran, Douglas C ; Mikochik, Peter J ; Li, Heng ; Naylor-Olsen, Adel ; Rudra, Sonali ; Trotter, B Wesley ; Hopkins, Tamara D ; Pop, Marius S ; Li, Huixu ; Lee, Christina ; Villagomez, Rosa A ; Day, Melinda A L ; Vacca, Joseph P ; McKeown, Michael R ; Hood, Tressa R ; Rioux, Nathalie ; Zhou, Minyun ; Gao, Hua ; Freeman, David B ; Bischofberger, Norbert ; Lin, Charles Y
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.