首次公开一种高效、高选择性的口服 KRAS G12V 抑制剂 PSTA-6208

Introduction: The KRAS G12V mutation is a major oncogenic driver in numerous cancers, promoting tumorigenesis and metastasis via constitutive activation of the MAPK pathway. Although the advent of KRAS-targeted therapy has yielded approved G12C inhibitors and clinical candidates for G12D and pan-KRAS inhibition, a significant unmet need remains for KRAS G12V-driven cancers. Here, we present PSTA-6208, a novel, orally bioavailable KRAS G12V inhibitor with sub-nanomolar cellular potency, marked efficacy in preclinical models, and high selectivity over wild-type KRAS, positioning it as a promising therapeutic candidate for KRAS G12V-positive tumors. Methods and Results: PSTA-6208 demonstrated potent and selective anti-proliferative activity in a panel of KRAS G12V-mutant cell lines, with IC₅₀ values around 0.1 nM in most cells. In head-to-head comparisons, PSTA-6208 was 17-fold more potent than RMC-5127. This activity was mechanistically linked to MAPK pathway suppression, as evidenced by inhibition of phospho-ERK in KRAS G12V-mutant CAPAN-1 cells (IC₅₀ = 1 nM). PSTA-6208 showed >500 folds selectivity over wild-type KRAS cells. PSTA-6208 exhibited favorable oral pharmacokinetics across multiple species, with low systemic clearance, a prolonged half-life (~10 hours), and high plasma exposure. These properties supported once-daily dosing, which achieved tumor regression in mice at doses as low as 3 mg/kg. PSTA-6208 induced profound, dose-dependent tumor growth inhibition and regression in multiple KRAS G12V xenograft models. In the NCI-H727 model, daily oral administration of PSTA-6208 at 1, 3, and 10 mg/kg for 21 days resulted in tumor growth inhibition (TGI) of 82%, 108%, and 112%, respectively. Notably, treatment with PSTA-6208 at 10 mg/kg led to near-complete tumor regression (complete response) by Day 21. All treatment groups were well-tolerated, with no significant adverse effects reported. Conclusions: PSTA-6208 is a potent, highly selective, and orally bioavailable KRAS G12V inhibitor. Its compelling preclinical profile-including sub-nanomolar cellular potency, exceptional selectivity, favorable pharmacokinetics, and robust in vivo efficacy culminating in tumor regression at low doses-strongly supports its further development as a clinical candidate for KRAS G12V-driven cancers.