Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers

SWI/SNF-related, matrix-associated,
actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2),
also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent
ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1),
also known as SMARCA4, are mutually exclusive ATPases of the large
ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional
regulation of gene expression. No small molecules have been reported
that modulate SWI/SNF chromatin-remodeling activity via inhibition
of its ATPase activity, an important goal given the well-established
dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric
dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene
expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These
compounds represent useful tools for understanding the functions of
BRM in BRG1-loss-of-function settings and should enable probing the
role of SWI/SNF functions more broadly in different cancer contexts
and those of other diseases.