FHT-1015 (FHT1015) is a potent, selective inhibitor of SMARCA4 and SMARCA2 (BRG1 and BRM) with IC50 of 4 and 5 nM respectively, the ATPase component of the BAF complex.
FHT-1015 displays no activity against the closely related ATPase CHD4 (IC50>400 uM).
SMARCA4 I1143M mutation confers resistance to FHT-1015.
FHT-1015 elicits lineage-specific effects on chromatin accessibility in treated cancer cells, causes reduced occupancy of master diseaseassociated transcription factors in 92-1 UM cells.
FHT-1015 affects the proliferation of many cancer cell types, and elicits rapid effects on UM, hematological cancer, and other cell lines inhibits the master transcription factor, SOX10, and its downstream transcriptional program, impacting cell survival and lineage specification.
FHT-1015 elicits tumor regression, demonstrating therapeutic utility in UM and perhaps other transcription factor-driven cancers.