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

J Med Chem. 2025 Jan 23;68(2):1772-1792. doi: 10.1021/acs.jmedchem.4c02535. Epub 2025 Jan 12.

Abstract

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.

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / metabolism
  • Administration, Oral
  • Allosteric Regulation / drug effects
  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacokinetics
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Biological Availability
  • Cell Line, Tumor
  • DNA Helicases* / antagonists & inhibitors
  • DNA Helicases* / metabolism
  • Drug Discovery
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / pathology
  • Melanoma / drug therapy
  • Melanoma / pathology
  • Mice
  • Nuclear Proteins* / antagonists & inhibitors
  • Nuclear Proteins* / metabolism
  • Rats
  • Structure-Activity Relationship
  • Transcription Factors* / antagonists & inhibitors
  • Transcription Factors* / metabolism
  • Uveal Neoplasms / drug therapy
  • Uveal Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Transcription Factors
  • SMARCA2 protein, human
  • Nuclear Proteins
  • DNA Helicases
  • Antineoplastic Agents
  • SMARCA4 protein, human
  • Adenosine Triphosphatases