Abstract 6376: KRASmultidegrader BPI-585725 displays potent anti-tumor activity in KRAS-driven preclinical models

Abstract As a prominent oncogenic driver, KRAS mutation is prevalent in approximately 20-30% of cancer patients, particularly in colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), where it accounts for roughly 45%, 90% and 35%, respectively. Although several KRAS G12C inhibitors are already on the market, they suffer from limited efficacy and short duration of response. Thus, eliminating the KRAS protein, rather than inhibiting KRAS holds hope for the long lasting clinical efficacy. Here, we introduce BPI-585725, a novel multiple KRAS (KRASmulti) proteolysis targeting chimera (PROTAC) molecular with a DC50 in nanomolar range. In cell-based KRAS degradation assays, BPI-585725 exhibited remarkable KRAS degradation property in KRAS G12C, G12D, G12V, G13D, and WT-Amplification (WTAmp) cell lines via a ubiquitin-proteasome system (UPS) dependent mechanism. BPI-585725 suppressed the proliferation of multiple KRAS driven cancer cell lines with an IC50 <10 nM, including those with G12X, G13D and WTAmp mutations. Additionally, binding assay revealed that BPI-585725 has >300-fold selectivity for KRAS compared to N/HRAS. In vivo, a single intravenous (IV) injection of 30 mg/kg BPI-585725 maintained drug concentration in tumor for up to 6 days, accompanied by sustained KRAS degradation and downstream DUSP6 inhibition. In multiple KRAS driven CDX models, weekly dosing of BPI-585725 dose dependently inhibited the tumor growth. In conclusion BPI-585725 is a highly potent and selective KRASmulti degrader with favorable pharmacokinetic properties, demonstrating a promising safety in preclinical studies. Citation Format: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Xiaoqiang Kong, Ying Zhao, Tao Zhang, Yanju Liu, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Haibo Chen, Lieming Ding, Hong Lan, Quan Zhou. KRASmultidegrader BPI-585725 displays potent anti-tumor activity in KRAS-driven preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6376.