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

作者：Xiang Ji, Chao Deng, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yu‐Wei 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 · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-1662 · 被引用次数：2 · 研究领域：Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis、Multiple Myeloma Research and Treatments

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 en...