Mechanistically, BRG1 promotes the interaction between SHP1 and PKM2, which affects the subcellular localization and pyruvate kinase activity of PKM2 by reducing its phosphorylation at tyrosine 105 and facilitating PKM2 tetramer formation. Thus, we explored a novel biological function of BRG1 in NSCLC, elucidated the impact of BRG1 on glucose metabolism, and provided insights for clinical strategies targeting tumors with this genetic mutation.

The pharmacologic inhibition of BRG1 using two selective inhibitors, BRM014 and FHD-286, revealed marked sensitivity in Ph-like B-ALL cell lines, whereas KMT2A -R B-ALL was resistant...These results support the advancement of BRG1-directed strategies as a viable treatment approach for patients with Ph-like B-ALL, with the potential to improve outcomes in this high-risk population. Higher levels of BRG1 correlate to poor clinical outcomes in Ph-like but KMT2A -R B-ALL Inhibition of BRG1 induces cell cycle arrest in Ph-like cells in vitro and extends the survival of mice in pre-clinical in vivo studies.

DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies.

P1, N=144, Active, not recruiting, Foghorn Therapeutics Inc. | Recruiting --> Active, not recruiting

IV-255 sensitised GBM cells to temozolomide (TMZ), the standard GBM treatment...IV-255 also sensitised GBM cells to TMZ-induced apoptosis, as shown by PARP and caspase-3 cleavage, which also requires Tyr1497. In conclusion, Tyr1497 within the BRD of BRG1 is critical for its interaction with IV-255 and for sensitising GBM cells to TMZ-induced DNA double-strand breaks and apoptotic cell death.

This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations.

In vivo, combined treatment with intermittent ATRi and continuous PARPi showed greater inhibition of tumor growth than ATRi alone in SMARCA4-deficient lung adenocarcinoma xenograft models. These findings demonstrate that PARPi-induced heterochromatin amplifies RS and ATRi susceptibility, providing a potential rationale for therapeutic strategies targeting SMARCA4-deficient tumors.

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.

This study reveals SMARCA2/4 as a DNA damage repair factor for double-strand break repair.

This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.

Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

P1, N=76, Terminated, Foghorn Therapeutics Inc. | N=125 --> 76 | Trial completion date: Aug 2025 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2023 --> Nov 2023; Sponsor terminated the study for business reasons.