SHR-RAS001的发现与鉴定：一种结构新颖、高效力的三元复合物RAS multi(ON)抑制剂

KRAS mutations serve as oncogenic drivers across roughly 20% of human malignancies, showing elevated occurrence in certain tumor types-most notably pancreatic cancer (~90%), alongside non-small cell lung cancer (~35%) and colorectal cancer (~45%). While currently available KRAS G12C inhibitors offer clinical benefit for that specific alteration, several other frequent KRAS variants, including G12D, G12V, G13D, and Q61H, remain largely untargeted and represent a persistent treatment gap. To address this need, we present SHR-RAS001, a structurally novel, highly potent cyclophilin A (CypA)-dependent tri-complex RAS multi (ON) inhibitor, specifically designed to counteract these currently difficult-to-treat RAS mutations. SHR-RAS001 effectively bound to CypA and subsequently recruited wild-type or mutant RAS proteins. The resulting ternary complex disrupted the interaction between RAF and active RAS, exhibiting potent cell-killing activity across a panel of RAS-mutant cell lines, with IC50 values below 1 nM. In RAS-mutant xenograft models, SHR-RAS001 demonstrated robust, dose-dependent antitumor activity and achieved significant tumor regression even at low dose levels. Furthermore, SHR-RAS001 displayed favorable in vitro ADME and safety profiles, including good stability in human hepatocytes, desirable physicochemical properties, , and low liabilities across both a 78-panel safety screen and a 97-kinase panel. SHR-RAS001 also exhibited promising pharmacokinetics, with dose-dependent exposure and acceptable oral bioavailability. Importantly, it showed favorable safety profiles in 14-day toxicology studies conducted in rats and dogs. In summary, SHR-RAS001 has been successfully developed as a novel, highly potent CypA-dependent tri-complex inhibitor of multiple RAS mutants. It demonstrates potent antitumor activity along with favorable pharmacokinetic and safety profiles. An open-label, multicenter Phase I study of SHR-RAS001 is currently underway.