Abstract 6050: Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707

Abstract

Abstract RAS oncogene mutations are prevalent in approximately 19% of cancer patients, with the most frequent alteration occurring in codon 12 of the KRAS gene, resulting in a variety of G12X oncoproteins. Recent advances in drug discovery have yielded several KRAS G12C inhibitors currently in clinical use, benefiting a subset of patients. However, addressing the high-prevalence G12D mutation remains a substantial unmet medical need. Targeted protein degradation using PROTAC molecules offers a promising approach for treating KRAS G12D-associated tumors, potentially providing superior efficacy and mitigating the development of resistance, a challenge frequently observed with KRAS G12C inhibitors in clinical settings. In the present study, we report a PROTAC compound RP03707 that efficiently induces the degradation of the KRAS G12D mutant protein and inhibits tumor growth. Treatment of AsPc-1 cells with RP03707 results in significant degradation of the KRAS G12D protein, with a DC50 value in the sub-nanomolar range. Within 24 hours, the compound eliminates over 90% of G12D proteins and effectively suppresses downstream cellular MAPK signaling. Additional in vitro experiments demonstrate that RP03707 inhibits cell proliferation in multiple KRAS G12D mutant cell lines, surpassing the anti-tumor efficacy of enzyme inhibitors. In a mouse GP2d xenograft tumor model, a single intravenous administration of RP03707 at 10 mpk results in excellent compound penetration and retention in tumor tissues, followed by 90% reduction of G12D protein levels for 7 days. Profound inhibition of tumor growth is observed not only in mouse GP2d xenograft but also in other mouse KRAS G12D tumor models, even when the compound is administered in low and infrequent doses. Moreover, RP03707 exhibits high selectivity for degrading the KRAS G12D protein and possesses favorable drug-like properties. RP03707, therefore, meets the criteria for advancing into drug development and represents a valuable therapeutic option for treating KRAS G12D-associated tumors. Citation Format: Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Jiaxin Zhou, Weihui Guo, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6050.