Abstract 4381: Preclinical studies of HEC211909, an orally bioavailable, high potent pan-KRAS inhibitor

Abstract Background: KRAS is the most commonly mutated oncogene, which is the driver in nearly 23% human cancers, and are especially prevalent in colorectal, lung, and pancreatic tumors. The KRAS signaling pathway is often hyperactivated in cancer cells due to KRAS gene mutations. This hyperactivation leads to uncontrolled cell proliferation, ultimately leading to the development and progression of cancer. There has been an urgent and unmet need to target KRAS mutations in KRAS-driven cancer. Methods: Biochemical HTRF assay was used to measure the inhibition of HEC211909 to both GDP-bound and GTP-bound state of various KRAS mutant. CellTiter-Glo assay was performed to determine the effects on proliferation of tumor cell lines. Several KRAS dependent tumor models were employed to study the in vivo pharmacodynamic and anti-tumor effects. Results: HEC211909 is a potent and orally bioavailable small molecule inhibitor of the KRAS oncogene, such as KRAS G12D, KRAS G12C, KRAS G12V, KRAS Q61H, KRAS G13D and KRAS wild-type amplifications. HEC211909 inhibits both active (GTP-bound) and inactive (GDP-bound) forms of multiple KRAS mutant protein with single-digit nanomolar IC50 values. HEC211909 has a strong anti-proliferative activity in a panel of KRAS mutant cancer cell lines and KRAS wild-type amplifications cancer cell lines in vitro with sub-nanomolar IC50 values, as well as significant inhibition of ERK1/2 phosphorylation with sub-nanomolar IC50 values. HEC211909 is highly selective for KRAS vs HRAS or NRAS, and is expected to be well-tolerated in normal tissues. In vivo, HEC211909 demonstrated dose-dependent anti-tumor activity with tumor regressions at 30 or 60 mg/kg given orally twice daily in KRAS-mutant xenograft models, such as PK59(KRAS G12D), HPAC(KRAS G12D), H358(KRAS G12C) xenograft models, and shows good tolerability during 21 days of treatment. Conclusions: HEC211909 is a highly potent and selective orally pan-KRAS(ON/OFF) inhibitor against KRAS G12D, KRAS G12C, KRAS G12V, KRAS Q61H, KRAS G13D mutations and also displays high selectivity over WT HRAS and NRAS, thus providing an expanded therapeutic index. Citation Format: Haiwang Liu, Hongming Xie, Fuxing Tan, Ning Kang, Ming Li, Yingjun Zhang. Preclinical studies of HEC211909, an orally bioavailable, high potent pan-KRAS inhibitor [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 4381.