Discovery and Characterization of RP03707: A Highly Potent and Selective KRAS<sup>G12D</sup> PROTAC
KRAS<sup>G12D</sup>, 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<sup>G12D</sup> protein degradation approach using the PROTAC technology for the treatment of KRAS<sup>G12D</sup> mutant tumors. Through the rational design of the KRAS<sup>G12D</sup> binder and proper selection of the linker and the E3 ligase ligand, we constructed PROTACs and identified <b>RP03707</b> as a CRBN-involving, highly potent, and selective KRAS<sup>G12D</sup> degrader. <b>RP03707</b> effectively inhibits tumor cell growth in multiple KRAS<sup>G12D</sup> cell lines. It also exhibits prolonged PK/PD effects and excellent efficacy in mouse CDX models bearing KRAS<sup>G12D</sup> tumors, highlighting its potential for the treatment of KRAS<sup>G12D</sup>-driven tumors in clinical settings.
Authors
- Xiang Ji (ORCID: https://orcid.org/0000-0002-8434-2328)
- Leduo Zhang (ORCID: https://orcid.org/0000-0002-0877-8621)
- Tianlun Zhou (ORCID: https://orcid.org/0000-0001-5864-0578)
- Chao Deng (ORCID: https://orcid.org/0000-0003-1147-5741)
- Honggui Zhou
- Qingyao Hu (ORCID: https://orcid.org/0000-0003-4579-445X)
- Youhong Wang (ORCID: https://orcid.org/0000-0001-8438-3149)
- Qiguo Zhang (ORCID: https://orcid.org/0000-0001-6539-8337)
- Huanping Li
- Qiming Fan (ORCID: https://orcid.org/0000-0001-8032-7414)
- Dawei Chen (ORCID: https://orcid.org/0000-0002-7486-1992)
- Liang Shen (ORCID: https://orcid.org/0000-0002-1818-1271)
- Xiaolin He
- Beibei Wang (ORCID: https://orcid.org/0000-0003-2362-2905)
- Shihao Sun (ORCID: https://orcid.org/0000-0002-1701-8114)
- Lin Wang (ORCID: https://orcid.org/0000-0002-0503-9727)
- Bing Bai (ORCID: https://orcid.org/0000-0002-1306-5343)
- Yijie Wang (ORCID: https://orcid.org/0009-0008-5131-9122)
- Zijun Chen (ORCID: https://orcid.org/0000-0003-2051-2938)
- Xiaojin Xu (ORCID: https://orcid.org/0000-0003-3542-1019)
- Chao Liang (ORCID: https://orcid.org/0000-0002-4716-8009)
- Yu‐Wei Zhang (ORCID: https://orcid.org/0000-0001-6566-5714)
- Jinchao Ai
- Jiasheng Lu (ORCID: https://orcid.org/0000-0003-3283-1231)
- Yanpeng Wu
- Xianqi Kong
- Bin Feng Zong
- Gang Wu
Institutions
- Fudan University (CN)
- Fosun Pharma (China) (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00428
- Citations
- 12
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 9.67