Discovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers

BRM (SMARCA2) and BRG1 (SMARCA4) are mutually exclusive
ATPase
subunits of the mSWI/SNF (BAF) chromatin remodeling complex. BAF is
an attractive therapeutic target because of its role in transcription,
and mutations in the subunits of BAF are common in cancer and neurological
disorders. Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual
ATPase subunits from a high-throughput screening hit with a BRM IC50 of ∼27 μM. FHD-286 is an orally
bioavailable compound with antitumor activity in mouse xenograft models
of uveal melanoma and acute myeloid leukemia and is being evaluated
in Phase 1 clinical trials.