Abstract 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 (IC50 = 6. 3 nM) and promotes the formation of the KRAS-BPI-585771-VHL ternary complex (EC50 = 8. 9 nM), while exhibiting strong selectivity over NRAS and HRAS (IC50 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 DC50 of approximately 1 nM, resulting in robust anti-proliferative activity (n = 48 tumor cell lines; IC50 10 nM in 32 cell lines; IC50 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. Citation Format: Zhengqing Li, Renqi Xu, Yanju Liu, Jiayu Zhao, Ying Zhao, Tianyi Ma, Tao Zhang, Bo Yan, Liang Chen, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Haibo Chen, Quan Zhou, Hong Lan, Li Mao, Lieming Ding. BPI-585771: A novel, potent pan-KRAS degrader with potent in vitro and in vivo efficacy in KRAS-driven tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB358.
Li et al. (Fri,) studied this question.