Abstract Background: The RAS oncogene, one of the most frequently mutated drivers in human cancer, is pathogenic in approximately 25% of malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma, colorectal carcinoma, and non-small cell lung cancer. Approved RAS inhibitors are predominantly limited to the KRAS G12C mutation, leaving a substantial patient population with other KRAS mutations (e.g., G12D, G12V, G13D, Q61R, etc.) or NRAS/HRAS mutations underserved. The emergence of resistance to these agents further underscores the critical need for broad-spectrum pan-RAS inhibitors. Methods: The affinity of HEC228032 for Cyclophilin A (CypA) and KRAS mutants (G12C/D/V, etc.), as well as its disruption of RAS-RAF interactions, was evaluated using HTRF binding assays. Its anti-proliferative activity was assessed via CTG assays in tumor cell lines. Pharmacodynamic and anti-tumor efficacy were investigated in multiple KRAS-dependent xenograft models in vivo. Results: HEC228032 exhibited high binding affinity for CypA and KRAS mutants (G12C, G12V, G12D, etc) and potently disrupted KRAS-RAF interactions. It demonstrated superior in vitro potency compared to RMC-6236, inhibiting proliferation across multiple RAS-mutant cell lines with sub-nanomolar IC50 values. In KRAS-mutant xenograft models (including PK59 (G12D), HPAC (G12D), and LU99 (G12C)), HEC228032 administered orally once daily at 3-10 mg/kg induced dose-dependent tumor regression, with good tolerability over 21 days. Furthermore, HEC228032 achieved higher oral exposure than RMC-6236 in mice, rats, and beagle dogs. Conclusions: HEC228032 is a promising pan-RAS(ON) inhibitor, characterized by potent antitumor activity against diverse RAS mutants, favorable pharmacokinetic properties, and an excellent tolerability profile, supporting its strong potential for clinical development. Citation Format: Haiwang Liu, Lingling Chen, Yangyang Meng, Hong Huang, Ming Li, Ning Kang, Yahui Feng, Ziting Liu, Jing Li, Kai Lin, Yingjun Zhang. HEC228032, an orally bioavailable molecular glue pan-RAS (ON) inhibitor with highly potent anti-tumor efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4570.
Liu et al. (Fri,) studied this question.