HEC228032：一种口服生物利用度良好的分子胶泛RAS(ON)抑制剂，具有高强度的抗肿瘤疗效

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.