Abstract 1769: A selective BRM (SMARCA2) inhibitor for the treatment of BRG1 (SMARCA4) mutant cancers

Abstract Background: ATP-dependent BRG1/BRM associated factor complexes play a key role in regulating gene expression by remodeling chromatin. BRG1 is mutated in ∼5% of all tumors, and in ∼7-10% of NSCLC tumors. BRM is essential for the growth of tumors that harbor loss of function BRG1 mutations. BRM and BRG1 ATPase share high protein-sequence homology (76% similarity), particularly in the ATPase domain (92% similarity). The Phase 1 clinical trial results of a BRG1/BRM dual inhibitor, in patients with BRG1 mutated cancers, showed potential safety risks. Improved safety margins may be achieved through the selective suppression of BRM activity. We identified a selective and potent BRM inhibitor (ZN-7035) with an excellent safety margin. Methods: The inhibition potency of ZN-7035 against isolated recombinant full-length BRM or BRG-1 ATPase activity was assessed by ADP-Glo assay. BRM-dependent KRT80 gene-expression in a BIG1-mutant NCI-H838 cell line was measured by Real-Time PCR. In vivo pharmacology was conducted to evaluate the efficacy of ZN-7035 oral administration monotherapy and in combination with a MCL1 inhibitor or chemotherapy in NCI-H838 NSCLC xenograft models. The pharmacokinetics of ZN-7035 was evaluated in mice, rats and dogs. The toxicity of ZN-7035 was assessed in 28-day orally administered repeat-dose studies in Sprague Dawley rats. Safety margins were determined based on the ratio of unbound AUC obtained from 28-day toxicology studies and predicted human PK at efficacious dose. Results: ZN-7035 exhibited strong inhibition (IC50=3.3 nM) against BRM ATPase as well as potent inhibition (IC50=8.3 nM) of KRT80 mRNA expression, a PD biomarker of BRM. ZN-7035 monotherapy demonstrated anti-tumor activity and synergistic tumor growth inhibition in combination with AMG176, a MCL1 inhibitor, in an NCI-H838 xenograft model carrying BRG1 loss-of-function mutation. KRT80 PD biomarker modulation in NCI-H838 established an exposure-response relationship. Further, ZN-7035 (20mg/kg) free concentration in plasma covers KRT80 IC90 for ∼17-19h and achieved 80% tumor inhibition. In addition, ZN-7035 demonstrated dose dependent anti-tumor activity and synergistic tumor growth inhibition in combination with chemotherapy in NSCLC xenograft models. In these studies, ZN-7035 demonstrated excellent pharmacokinetic and safety properties. Due to good BRG1 selectivity, ZN-7035 was well tolerated in rats at 120 mg/kg/day following repeat dosing for 28 days. Based on DMPK and rat DRF data, the predicted human efficacious dose is 115 mg BID, and the predicted human safety margin is >30-fold. Conclusion: ZN-7035 is a highly potent, selective, orally available, small-molecule, enzymatic inhibitor of BRM. Preclinical findings highlight that ZN-7035-based combination therapies have the potential to be effective and safe treatments for patients with tumors harboring BRG1 mutations. Citation Format: Ding Zhou, Zheng Wang, Yan Liu, Tingting Fu, Zack Cheng. A selective BRM (SMARCA2) inhibitor for the treatment of BRG1 (SMARCA4) mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1769.