Discovery and Characterization of Small Molecule Inhibitors of SWI/SNF ATPase Activity in BRG1/SMARCA4-Deficient Non-Small Cell Lung Cancers

Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes across various cancers informing critical roles of their dysregulation towards the malignant state. While elucidating the mechanisms of SWI/SNF mutations remains a significant area of investigation, recent studies have also revealed an important role for the remaining SWI/SNF activity in supporting the growth of SWI/SNF-mutant cancers. In particular, the discovery of synthetic lethality between BRM/SMARCA2 and BRG1/SMARCA4, the highly homologous and mutually exclusive catalytic subunits of SWI/SNF complexes, has driven great interest in pursuing the therapeutic targeting of BRM in BRG1-mutant/deficient cancers. We report for the first time the discovery and functional characterization of allosteric small molecule dual inhibitors of BRM and BRG1 ATPase activity. BRM011 and its structurally related analogs display cellular activity in modulating BRM-dependent gene expression and inducing growth inhibition in BRG1-mutant lung cancer models. Genome wide assessments show that BRM011 treatment induces specific changes in chromatin accessibility and gene expression profiles similar to genetic depletion of BRM. Overall, these studies not only elucidate the previously unexplored feasibility of chemically modulating the enzymatic activity of such a complex and unprecedented target, but also provide fundamental tools for further dissecting SWI/SNF function in cancers, normal tissues and other disease contexts.