First disclosure of a highly potent and selective oral KRAS G12V inhibitor PSTA-6208
Presenter: Chi-Chung Chan, PhD Session: Novel Antitumor Agents 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Wenxi Li , Lihong Hu , zhenzhen Zhu , Yingchun Liu , Tao Yu , Qianwei Jiang , Chi-Chung Chan , Jian Li , Shuhui Chen Prospect Therapeutics, Nanjing, China
Abstract
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.
Disclosure
W. Li, None.. L. Hu, None.. Z. Zhu, None.. Y. Liu, None.. T. Yu, None.. Q. Jiang, None.. C. Chan, None.. J. Li, None.. S. Chen, None.
Cited in
Control: 2810 · Presentation Id: 8815 · Meeting 21436