Cyclin-dependent kinase 9, or CDK9, serves as a key regulator of several cancer-promoting transcriptional programs, including those driven by MCL1, MYC, and MYB. Inhibition of CDK9 has emerged as an attractive therapeutic approach to producing synthetic lethality in genomically-selected cancers, and several non-selective CDK9 inhibitors in development have demonstrated activity in multiple tumor types. However, the approach has been significantly limited due to adverse effects associated with broad kinase inhibition and in turn, a narrow therapeutic window.
SMARCA2 and SMARCA4 (also known as BRM and BRG1, respectively) are enzymatic subunits involved in the regulation of gene expression through chromatin remodeling. SMARCA4 has been shown to be mutated in multiple cancers, including 10-12% of non-small cell lung cancer (NSCLC). Because the activity of either SMARCA2 or SMARCA4 is required for chromatin remodeling to occur, SMARCA4-deficient cancer cells become highly dependent on SMARCA2 for their survival. Targeting SMARCA2 in SMARCA4-deficient cancers is believed to produce a strong synthetic lethality, resulting in SMARCA4-mutant tumor cell death while sparing normal cells that express SMARCA4 protein. However, structural similarities between the two have historically posed challenges for selective SMARCA2 inhibition.