Abstract 4620: RCZY-698: An orally bioavailable, highly potent, and selective reversible KRASG12V (ON)-state inhibitor with robust antitumor activity in preclinical models of KRASG12V-driven solid tumors

Abstract The KRASG12V mutation is the second most common oncogenic RAS alteration, particularly as a driver mutation in pancreatic (∼34%), colorectal (∼21%), and non-small cell lung cancers (∼5%). It is associated with poor prognosis in affected cancer patients. Due to its very low GTPase activity, which impairs hydrolysis of RAS-bound GTP to RAS-bound GDP, the mutant protein spends most of its time in the active (GTP-bound) state with limited cycling. As a result, an off-state KRASG12V inhibitor targeting the conformation of GDP-bound (inactive) state would theoretically be ineffective at blocking downstream signaling pathways such as MAPK and PI3K-AKT, as the mutant protein rarely accesses its GDP-bound state. The lack of a nucleophilic side chain at position 12 (valine) of KRASG12V precludes development of covalent inhibitors targeting the mutation site directly. Currently, no direct inhibitors targeting KRASG12V have been approved, representing a significant unmet medical need. RCZY-698, developed by Rongchang Pharmaceuticals, is a novel, highly potent, orally bioavailable, and mutant-selective non-covalent tri-complex inhibitor that specifically targets the GTP-bound (ON) conformation of KRASG12V. It potently disrupts the interaction between KRASG12V and downstream effector proteins, thereby robustly suppressing key signaling cascades, including the MAPK pathway mechanistically, RCZY-698 engages cyclophilin A (CypA) specifically to form a stable ternary complex with KRASG12V, conferring exceptional selectivity over wild-type KRAS. In a panel of KRASG12V-mutant tumor cell lines, RCZY-698 elicits potent antiproliferative effects, demonstrating superior in vitro growth inhibition compared with RMC-5127. This compound exhibits favorable in vitro absorption, distribution, metabolism, and excretion (ADME) characteristics, alongside distinctive oral pharmacokinetic profiles across multiple species. In human KRASG12V-mutant xenograft models, RCZY-698 induces dose-dependent tumor regression at well-tolerated doses, achieving comparable tumor growth inhibition (TGI) to RMC-5127 at substantially lower exposures. Collectively, these data delineate the discovery and preclinical profiling of RCZY-698 as a novel oral non-covalent KRASG12V(ON)-selective tri-complex inhibitor with compelling in vitro potency and in vivo efficacy. Further efforts and characterization work are being implemented to complete the preclinical candidate (PCC) data package for RCZY-698. Citation Format: Xiaojing (Celia) Chen, Lin Wang, Xiaohong Liu, Zhengyong Wan, Qiaoni You, Jianming Bao, . RCZY-698: An orally bioavailable, highly potent, and selective reversible KRASG12V (ON)-state inhibitor with robust antitumor activity in preclinical models of KRASG12V-driven solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4620.