Journal article

A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies

Darren C Phillips, Sha Jin, Gareth P Gregory, Qi Zhang, John Xue, Xiaoxian Zhao, Jun Chen, Yunsong Tong, Haichao Zhang, Morey Smith, Stephen K Tahir, Rick F Clark, Thomas D Penning, Jennifer R Devlin, Jake Shortt, Eric D Hsi, Daniel H Albert, Marina Konopleva, Ricky W Johnstone, Joel D Leverson Show all

Leukemia | NATURE PUBLISHING GROUP | Published : 2020

Abstract

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 p..

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