RCZY-869：一种高效、选择性、口服生物利用度高的共价KRAS G12D（ON状态）抑制剂，在KRAS G12D驱动的实体瘤临床前模型中具有强健的抗肿瘤活性

KRAS G12D is the most prevalent oncogenic mutation in the RAS family. Among common solid tumors, it drives approximately 40% of pancreatic ductal adenocarcinoma (PDAC), 15% of colorectal cancer (CRC), and 5% of non-small cell lung cancer (NSCLC) cases, underscoring a significant unmet clinical need for targeted therapies. To date, no direct KRAS G12D inhibitors have received global regulatory approval, highlighting the pressing demand for effective agents. In KRAS G12D , the G12D substitution reduces RAS-bound GTP hydrolysis rate by ~2-fold compared to wild-type KRAS (and even more relative to KRAS G12C ), resulting in a higher proportion of KRAS G12D existing in the GTP-bound conformation within cancer cells. This makes the “ON” state the dominant, therapeutically relevant form driving oncogenesis. Inhibiting this active, GTP-bound pool directly disrupts the core signaling activity, potentially yielding greater efficacy than targeting the transient “OFF” state. This mechanism supports targeting the GTP-bound conformation as a strategy with high clinical benefit potential. Emerging KRAS G12D inhibitors target OFF, ON, or both states. Phase 1/1b data show ON-state inhibitor RMC-9805 and ON/OFF inhibitor VS-7375 (GFH375) have comparable objective response rates (ORR) and disease control rates (DCR) in NSCLC at their respective recommended Phase 2 doses (RP2D). In PDAC, VS-7375 had marginally higher ORR/DCR (52%/100% vs. 30%/80% for RMC-9805), but RMC-9805 had superior safety: low dose modification rates, no grade 4/5 TRAEs (predominantly grade 1 toxicities), and no DLTs. VS-7375 had a ~4-fold higher discontinuation rate, with 27.5% of patients experiencing grade 3/4 TRAEs. To address these challenges, Rongchang Pharmaceuticals has developed RCZY-869, a highly potent, selective, and orally bioavailable covalent tri-complex inhibitor that specifically targets the GTP-bound (ON) state of KRAS G12D . It engages cyclophilin A (CypA) to form a stable ternary complex with KRAS G12D (ON), blocking downstream effectors and suppressing MAPK signaling. RCZY-869 exhibits significantly greater in vitro antiproliferative activity than RMC-9805 across KRAS G12D -mutant cell lines, favorable ADME properties, and superior oral PK in preclinical species. In KRAS G12D xenograft models, it delivers dose-dependent antitumor effects at well-tolerated doses, achieving tumor growth inhibition (TGI) comparable to RMC-9805 but at substantially lower exposures. These findings position RCZY-869 as a novel ON-state-selective KRAS G12D inhibitor with compelling preclinical potency and efficacy. Ongoing characterization advances its candidate package to support clinical development.