BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor

BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPases of chromatin remodeling BAF (BRG1/BRM-associated factor) complexes, which enable transcription factors/co-factors to modulate gene-expressions, mediating growth, differentiation-arrest and survival of AML cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although monotherapy with Menin inhibitor (MI) induces clinical remissions, most patients either fail to respond or relapse. FHD-286 is a selective BRG1/BRM inhibitor, undergoing clinical development in AML. Here, FHD-286 induced differentiation and lethality in AML cells with MLL1r or mtNPM1, reducing chromatin accessibility and repressing c-Myc, PU.1 and CDK4/6. Whereas FHD-286 monotherapy reduced AML burden, leukemia-initiating potential and improved survival, FHD-286 combinations with MI, BET inhibitor, decitabine or venetoclax was significantly more effective in reducing AML burden and improved survival, without significant toxicity, in xenograft models of AML with MLL1r or mtNPM1. These findings highlight promising FHD-286-based combinations for therapy of AML with MLL1r or mtNPM1. Statement of Significance Inhibition of BRG1/BRM ATPases by FHD-286 reduced chromatin accessibility, repressed c-Myc, PU.1 and CDK4/6, inducing differentiation, leukemia-initiating potential and lethality in AML stem-progenitor cells. FHD-286-based combinations with Menin or BET inhibitor or decitabine reduced AML burden and improved survival in xenograft models of AML with MLL rearrangement or mutant NPM1. ### Competing Interest Statement Kapil N. Bhalla has received research funding from Iterion, Foghorn and Nurix Pharmaceuticals, and he serves as a consultant for Iterion Therapeutics. Jessica Piel, Mike Collins and Murphy Hentemann are employed by Foghorn Therapeutics. Rwik Sen is an employee of Active Motif. All other authors declare they have no conflict of interests to disclose.