BPI-585771: A novel, potent pan-KRAS degrader with potent in vitro and in vivo efficacy in KRAS-driven tumors
Presenter: Renqi Xu, PhD Session: Late-Breaking Research: Experimental and Molecular Therapeutics 3 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
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 Betta Pharmaceuticals, Co., LTD., Hangzhou, China
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 (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 50 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.
Disclosure
Z. Li, None.. R. Xu, None.. Y. Liu, None.. J. Zhao, None.. Y. Zhao, None.. T. Ma, None.. T. Zhang, None.. B. Yan, None.. L. Chen, None.. J. Guo, None.. C. Yang, None.. H. Han, None.. X. Liu, None.. H. Chen, None.. Q. Zhou, None.. H. Lan, None.. L. Mao, None.. L. Ding, None.
Cited in
Control: 10521 · Presentation Id: 11465 · Meeting 21436