RCZY-698：一种口服生物可利用、高效力、选择性的可逆KRAS G12V（ON）状态抑制剂，在KRAS G12V驱动的实体瘤临床前模型中具有强健的抗肿瘤活性

The KRAS G12V 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 KRAS G12V 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 KRAS G12V precludes development of covalent inhibitors targeting the mutation site directly. Currently, no direct inhibitors targeting KRAS G12V 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 KRAS G12V . It potently disrupts the interaction between KRAS G12V 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 KRAS G12V , conferring exceptional selectivity over wild-type KRAS. In a panel of KRAS G12V -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 KRAS G12V -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 KRAS G12V (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.