高效、选择性KRASG12D PROTAC RP03707的发现与表征

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-05-08 DOI:10.1021/acs.jmedchem.5c00428

Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bin Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Chao Deng, Liqiang Shen, Zijun Chen, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Xianqi Kong, Jiasheng Lu

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引用次数: 0

摘要

KRASG12D是kras相关肿瘤中最普遍的致癌突变，是一种备受追捧的癌症治疗药物靶点。在这项研究中，我们利用PROTAC技术探索了KRASG12D蛋白降解方法，用于治疗KRASG12D突变肿瘤。通过合理设计KRASG12D结合剂，合理选择连接剂和E3连接酶配体，我们构建了PROTACs，并鉴定了RP03707是一个涉及crbn的、高效的、选择性的KRASG12D降解物。RP03707在多种KRASG12D细胞系中能有效抑制肿瘤细胞生长。它在KRASG12D肿瘤小鼠CDX模型中也表现出持久的PK/PD效应和出色的疗效，突出了其在临床治疗KRASG12D驱动肿瘤的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery and Characterization of RP03707: A Highly Potent and Selective KRASG12D PROTAC

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Discovery and Characterization of RP03707: A Highly Potent and Selective KRASG12D PROTAC

KRAS^G12D, 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^G12D protein degradation approach using the PROTAC technology for the treatment of KRAS^G12D mutant tumors. Through the rational design of the KRAS^G12D binder and proper selection of the linker and the E3 ligase ligand, we constructed PROTACs and identified RP03707 as a CRBN-involving, highly potent, and selective KRAS^G12D degrader. RP03707 effectively inhibits tumor cell growth in multiple KRAS^G12D cell lines. It also exhibits prolonged PK/PD effects and excellent efficacy in mouse CDX models bearing KRAS^G12D tumors, highlighting its potential for the treatment of KRAS^G12D-driven tumors in clinical settings.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.