Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant
Covalent warheads are indispensable in the design and development of targeted covalent inhibitors (TCIs). Here, we designed and evaluated acyl diazo probes as an aspartic acid/glutamic acid targeted warhead. Among these probes, <b>P1</b> demonstrated chemoselectivity for carboxyl residues, even under complex physiological conditions, effectively modifying the proteome in both cell lysates and live cells. Subsequently, we incorporated the warhead onto MRTX-1133, a potent ligand of the KRAS (G12D) mutant, to generate a novel TCI called <b>KN2-H</b>. Compared with other mutants, <b>KN2-H</b> demonstrated covalent modification specifically targeting the KRAS (G12D) mutant, with notable chemoselectivity. It also possessed strong antiproliferative activity against KRAS (G12D) mutant cell lines by downregulating RAS oncogenic signaling. Our findings provide a novel strategy for designing novel TCIs targeting carboxyl residues, based on acyl diazo warheads.
Authors
- Lu Zhou (ORCID: https://orcid.org/0000-0002-6807-2647)
- Tianping Shuai
- Zi-Hang Yuan
- Zhongjiao Fan
- Huabo Su (ORCID: https://orcid.org/0000-0002-8475-2685)
- Xiaoxue Ruan
- Motonari Uesugi (ORCID: https://orcid.org/0000-0002-8515-445X)
- Zhibei Qu (ORCID: https://orcid.org/0000-0003-1517-0822)
- Minjia Tan (ORCID: https://orcid.org/0000-0002-6784-9653)
- Ping Liu (ORCID: https://orcid.org/0000-0003-1309-570X)
- Rong Zhang (ORCID: https://orcid.org/0000-0003-2941-4808)
- Wenhao Xie (ORCID: https://orcid.org/0000-0001-6132-5480)
- Qing Li (ORCID: https://orcid.org/0009-0006-5263-4277)
- Zhiyuan Qi
- Mingya Zhang (ORCID: https://orcid.org/0000-0002-9712-2711)
Institutions
- Anhui Medical University (CN)
- Chinese Academy of Sciences (CN)
- Kyoto University (JP)
- Fudan University (CN)
- Aurora West Allis Medical Center (US)
- SAIC-GM (China) (CN)
- Immunité et Cancer (FR)
- Shanghai Institute of Materia Medica (CN)
- Zhongshan Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Instituto de Investigaciones Químicas (ES)
- State Key Laboratory of Drug Research
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01365
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00