Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant
文献类型：期刊论文
| 作者 | Shuai, Tianbai5; Zhang, Rong5; Yuan, Zihang4,5; Zhang, Mingya3,5; Fan, Zhongjiao5; Ruan, Xiaoxue5; Qi, Zhiyuan5; Xie, Wenhao5; Liu, Ping3; Uesugi, Motonari1,2,5 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2025-10-23 |
| 卷号 | 68期号:20页码:21427-21440 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c01365 |
| 英文摘要 | 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, P1 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 KN2-H. Compared with other mutants, KN2-H 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. |
| WOS关键词 | AMG 510 ; INHIBITORS ; REAGENTS ; BEARING |
| 资助项目 | National Natural Science Foundation of China ; Shanghai Advanced Research Institute, Chinese Academy of Science, China ; Core Facility of Shanghai Medical College, Fudan University |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001583669100001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321597]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Tan, Minjia; Su, Hua; Zhou, Lu |
| 作者单位 | 1.Kyoto Univ, Inst Chem Res, Uji, Kyoto 6110011, Japan 2.Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Uji, Kyoto 6110011, Japan 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Anhui Med Univ, Affiliated Hosp 1, Innovat Inst Tumor Immun & Med ITIM, Dept Hepatobiliary Surg,Anhui Prov Key Lab Tumor I, Hefei 230022, Peoples R China 5.Fudan Univ, Zhongshan Hosp, Sch Pharm, Liver Canc Inst,Inst Biomed Sci, R China, Shanghai 200001, Peoples R China 6.Shanghai Allist Pharmaceut Co Ltd, Shanghai 200001, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shuai, Tianbai,Zhang, Rong,Yuan, Zihang,et al. Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(20):21427-21440. |
| APA | Shuai, Tianbai.,Zhang, Rong.,Yuan, Zihang.,Zhang, Mingya.,Fan, Zhongjiao.,...&Zhou, Lu.(2025).Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant.JOURNAL OF MEDICINAL CHEMISTRY,68(20),21427-21440. |
| MLA | Shuai, Tianbai,et al."Expanding the Chemistry of Acyl Diazo Electrophile as a Tunable Warhead for Covalent Targeting of KRAS (G12D) Mutant".JOURNAL OF MEDICINAL CHEMISTRY 68.20(2025):21427-21440. |
入库方式： OAI收割
来源：上海药物研究所
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