BPI-585771：一种新型强效泛KRAS降解剂，在KRAS驱动的肿瘤中具有强效的体外和体内疗效

The therapeutic landscape for KRAS-driven cancers has rapidly expanded from G12C-selective inhibitors to pan-KRAS approaches, including small-molecule inhibitors, targeted protein degraders, and tri-complex-based modalities. Substantial unmet medical needs persist, particularly in tumors driven by KRAS wild-type amplification and in tumors with acquired resistance from previous KRAS targeted therapies. Pan-KRAS degraders have therefore emerged as a promising strategy to bridge these gaps, offering broad mutation coverage with potential for improved efficacy and safety. Here, we present BPI-585771, a highly potent and selective PROTAC designed to induce degradation of multiple KRAS mutants as well as the wild-type KRAS, but not the NRAS or HRAS. Mechanistically, BPI-585771 binds KRAS with high affinity (IC 50 = 6.3 nM) and promotes the formation of the KRAS-BPI-585771-VHL ternary complex (EC 50 = 8.9 nM), while exhibiting strong selectivity over NRAS and HRAS (IC 50 > 1000 nM for each). Across a broad panel of KRAS-driven cancer cell lines, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC), BPI-585771 potently and completely degrades mutant and wild-type KRAS, with a DC 50 of approximately 1 nM, resulting in robust anti-proliferative activity (n = 48 tumor cell lines; IC 50 < 10 nM in 32 cell lines; IC 50 < 100 nM in 42 cell lines). In multiple in vivo efficacy models, BPI-585771 demonstrates marked antitumor efficacy, inducing deep and durable tumor regressions with a convenient once-weekly dosing regimen (30 mg/kg, QW). Notably, treatment significantly reverses cancer-cachexia-associated body-weight loss, potentially highlighting an additional therapeutic benefit. Furthermore, BPI-585771 exhibits favorable pharmacokinetic properties and an encouraging preliminary toxicity profile, supporting its advancement into IND-enabling studies and subsequent clinical development. Currently, IND-enabling studies for BPI-585771 are ongoing, and IND submission is expected in Q4 2026.