Abstract 1662: Preclinical studies of RP04340: an orally available and potent PROTAC compound targeting KRAS G12C/D/V mutant tumors

Mutations in the RAS oncogene are highly prevalent in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and lung adenocarcinoma (LUAD), with codon 12 of the KRAS gene being the most frequently altered site. Substitutions of glycine at codon 12 to cysteine (G12C), glutamate (G12D), or valine (G12V) occur in 66.3%, 23.7%, and 24.4% of PDAC, CRC, and LUAD patients, respectively. While recently approved drugs targeting KRAS G12C mutation have shown clinical benefit, there remains a significant unmet need for therapies addressing the highly prevalent G12D and G12V mutations. Proteolysis-targeting chimeras (PROTACs) represent a novel therapeutic strategy for the targeted degradation of oncogenic proteins, potentially offering superior efficacy and mitigating resistance. In this study, we present RP04340, a potent and orally bioavailable PROTAC compound that selectively degrades KRAS G12C/D/V proteins and demonstrates robust anti-tumor activity. RP04340 induced significant degradation of KRAS G12C, KRAS G12D, and KRAS G12V proteins in cell lines Miapaca-2, PK-59, and NCI-H727, respectively, with a 50% degradation concentration (DC50) in the low nanomolar range. Within 12 hours of treatment, RP04340 reduced KRAS G12C/D/V protein levels by over 80% and effectively suppressed downstream signaling pathways, including pERK and DUSP6. Additionally, RP04340 inhibited cell proliferation in multiple KRAS G12C/D/V mutant cell lines, surpassing the anti-tumor efficacy of its enzymatic inhibitor warhead. In vivo studies using mouse xenograft models (Miapaca-2, PK-59, and NCI-H727) demonstrated significant tumor growth inhibition following daily oral administration of RP04340 at doses of 25, 50, and 100 mg/kg, with a clear dose-response relationship. Pharmacokinetic analyses revealed that RP04340 accumulated preferentially in tumor tissues, achieving high intratumoral concentrations with repeated dosing. Furthermore, tissue distribution studies in mouse showed significant accumulation of RP04340 in the lungs and pancreas after 15 days of consecutive dosing, supporting its suitability for treating cancers in these organs. In conclusion, RP04340, a PROTAC compound with compelling preclinical efficacy and favorable pharmacokinetic properties, represents a promising therapeutic candidate for KRAS G12C/D/V-driven cancers. Citation Format: Xiang Ji, Chao Deng, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Huanping Li, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Xianqi Kong, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Preclinical studies of RP04340: an orally available and potent PROTAC compound targeting KRAS G12C/D/V mutant tumors [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 1662.