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.