SMARCA4/SMARCA2 (BRG1/BRM ATPase subunits)

Class

Small molecule allosteric ATPase inhibitor

Pathway

SWI/SNF (BAF) chromatin remodeling complex

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two alternative catalytic ATPase subunits of the SWI/SNF (BAF) complex, a multiprotein machine that uses energy from ATP hydrolysis to slide and reposition nucleosomes along DNA. By opening or closing chromatin at specific loci, SWI/SNF controls which genes are accessible to transcription factors, making it a central regulator of gene expression programs involved in cell identity, proliferation, and differentiation. Only one of the two ATPase subunits is typically incorporated into a given BAF complex, and cells can often substitute one for the other. Many cancers become abnormally dependent on SWI/SNF activity to sustain oncogenic transcriptional programs, and some tumors that have lost one subunit (through mutation) become selectively reliant on the remaining paralog for survival. Small-molecule allosteric ATPase inhibitors that block both SMARCA4 and SMARCA2 are designed to shut down BAF-driven transcription comprehensively, preventing tumor cells from evading inhibition by switching to the untargeted paralog. This dual-targeting strategy is broadly relevant to cancers with paralog dependency or SWI/SNF pathway dysregulation, though because chromatin remodeling is essential in normal tissue, careful attention to tolerability is required.