Abstract 4379: BPI-572270: An orally bioavailable and highly potent RAS (On) multi tri-complex inhibitor

Abstract KRAS mutations are oncogenic drivers occur in approximately 20%-30% of all cancers with particularly high frequencies observed in pancreatic cancer (∼90%), non-small cell lung cancer (∼35%), and colorectal cancer (∼45%). While approved KRASG12C inhibitors have demonstrated clinical benefits in patients with KARSG12C mutation, other prevalent KRAS mutations, such as KRASG12D/G12V/G13D/Q61H, remain a significant therapeutic challenge. Here we present BPI-572270, a highly potent Cyclophilin A-dependent RAS(On)multi inhibitor with favorable oral bioavailability designed to target those difficult-to-treat RAS mutations. In vitro, BPI-572270 demonstrated exceptional potency by disrupting the GTP bound RASWT/Mut and cRAF interaction in a cell-free assay, and by inhibiting tumor cell proliferation with sub-nanomolar IC50 values in a range of tumor cell lines harboring mutant KRAS, NRAS, or HRAS, as well as wild type RAS cell lines. In vivo, BPI-572270 achieved significant tumor regression in KRASG12V human pancreatic Capan-2 xenograft mouse model at 0.3 mg/kg (PO, QD), and in KRASG12D human pancreatic KP-4 xenograft model at 3 mg/kg (PO, QD), demonstrating potent efficacy. BPI-572270 also showed outstanding pharmacokinetic properties in mouse, rat and beagle dog. Safety evaluations in repeated-dose studies in rats and beagle dogs indicate a promising safety profile, reinforcing its potential for further clinical development. In conclusion, BPI-572270 emerges as a highly potent, orally bioavailable RAS(On)multi inhibitor, with favorable efficacy, pharmacokinetics, and safety profiles in pre-clinical studies. Citation Format: Xiang Yang, Xiaoguan Zhu, Han Han, Wenmao Wu, Yuzheng Zhou, Xiaoqiang Kong, Ying Zhao, Xiaoyun Liu, Yanju Liu, Tao Zhang, Haibo Chen, Shusen Li, Cheng Yang, Jing Guo, Quan Zhou, Hong Lan, Lieming Ding. BPI-572270: An orally bioavailable and highly potent RAS (On) multi tri-complex inhibitor [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 4379.