HEC228032, an orally bioavailable molecular glue pan-RAS (ON) inhibitor with highly potent anti-tumor efficacy
Presenter: Haiwang Liu, PhD Session: Novel Antitumor Agents 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Haiwang Liu , Lingling Chen , Yangyang Meng , Hong Huang , Ming Li , Ning Kang , Yahui Feng , Ziting Liu , Jing Li , Kai Lin , Yingjun Zhang HEC Pharma Co. Ltd, Shenzhen, China
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.
Disclosure
H. Liu, Sunshine Lake Pharma Co., Ltd. Employment, Stock. L. Chen, Sunshine Lake Pharma Co., Ltd. Employment. Y. Meng, Sunshine Lake Pharma Co., Ltd. Employment. H. Huang, Sunshine Lake Pharma Co., Ltd. Employment. M. Li, Sunshine Lake Pharma Co., Ltd. Employment, Stock. N. Kang, Sunshine Lake Pharma Co., Ltd. Employment, Stock. Y. Feng, Sunshine Lake Pharma Co., Ltd. Employment, Stock. Z. Liu, Sunshine Lake Pharma Co., Ltd. Employment. J. Li, Sunshine Lake Pharma Co., Ltd. Employment, Stock. K. Lin, Sunshine Lake Pharma Co., Ltd. Employment. Y. Zhang, Sunshine Lake Pharma Co., Ltd. Employment, Stock.
Cited in
Control: 3398 · Presentation Id: 8828 · Meeting 21436