Ji Xiang, Li Huanping, Wu Gang, Zhang Qiguo, He Xiaolin, Wu Yanpeng, Zong Bin, Xu Xiaojin, Liang Chao, Wang Beibei, Zhang Yuwei, Hu Qingyao, Deng Chao, Shen Liqiang, Chen Zijun, Bai Bing, Wang Lin, Ai Jinchao, Zhang Leduo, Zhou Honggui, Sun Shihao, Wang Yijie, Wang Youhong, Fan Qiming, Chen Dawei, Zhou Tianlun, Kong Xianqi, Lu Jiasheng
Risen (Shanghai) Pharma Tech Co., Ltd., Shanghai 201210, China.
School of Life Sciences, Fudan University, Shanghai 200437, China.
J Med Chem. 2025 May 22;68(10):10238-10254. doi: 10.1021/acs.jmedchem.5c00428. Epub 2025 May 8.
KRAS, the most prevalent oncogenic mutation in KRAS-associated tumors, represents a highly sought-after drug target for cancer treatment. In this study, we explored a KRAS protein degradation approach using the PROTAC technology for the treatment of KRAS mutant tumors. Through the rational design of the KRAS binder and proper selection of the linker and the E3 ligase ligand, we constructed PROTACs and identified as a CRBN-involving, highly potent, and selective KRAS degrader. effectively inhibits tumor cell growth in multiple KRAS cell lines. It also exhibits prolonged PK/PD effects and excellent efficacy in mouse CDX models bearing KRAS tumors, highlighting its potential for the treatment of KRAS-driven tumors in clinical settings.
KRAS是KRAS相关肿瘤中最常见的致癌突变，是癌症治疗中备受追捧的药物靶点。在本研究中，我们探索了一种使用PROTAC技术降解KRAS蛋白的方法来治疗KRAS突变肿瘤。通过合理设计KRAS结合剂、适当选择连接子和E3连接酶配体，我们构建了PROTACs，并鉴定出一种涉及CRBN、高效且具有选择性的KRAS降解剂。该降解剂能有效抑制多种KRAS细胞系中的肿瘤细胞生长。在携带KRAS肿瘤的小鼠CDX模型中，它还表现出延长的药代动力学/药效学效应和优异的疗效，凸显了其在临床环境中治疗KRAS驱动肿瘤的潜力。
