A Self-Assembled Nano-Molecular Glue (Nano-mGlu) Enables GSH/H2O2-Triggered Targeted Protein Degradation in Cancer Therapy
文献类型：期刊论文
| 作者 | Sun, Jie5,6; Gu, Mingxi6; Peng, Lvyang6; Guo, Jing3; Chen, Peng4,6; Wen, Yalei3; Feng, Fang2; Chen, Xiaojuan1; Liu, Tongzheng3; Chen, Yongheng1 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
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| 出版日期 | 2024-12-20 |
| 卷号 | 147期号:1页码:372-383 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.4c11003 |
| 通讯作者 | Lu, Xiaoyun(luxy2016@jnu.edu.cn) ; Gao, Liqian(gaolq@mail.sysu.edu.cn) ; Yao, Shao Q.(chmyaosq@nus.edu.sg) ; Yuan, Peiyan(yuanp3@mail.sysu.edu.cn) |
| 英文摘要 | Molecular glues are promising protein-degrading agents that hold great therapeutic potential but face significant challenges in rational design, effective synthesis, and precise targeting of tumor sites. In this study, we first overcame some of these limitations by introducing a fumarate-based molecular glue handle onto specific ligands of therapeutic kinases (TBK1, FGFR, and Bcr-Abl), resulting in the effective degradation of these important cancer targets. Despite the broad applicability of the strategy, we unexpectedly discovered potent and widespread cytotoxicity across various cell lines, including noncancerous ones, rendering it less effective in cancer therapy. To address this critical issue, we next developed a self-assembled nanoparticle-based molecular glue (nano-mGlu) based on one of the newly discovered Bcr-Abl-degrading molecular glues (H1-mGlu). We showed that the resulting nano-mGlu (named Cle-NP) was able to release H1-mGlu in vitro in the presence of a high concentration of GSH or H2O2 (commonly found in the tumor microenvironment). Subsequent in vivo antitumor studies with a K562-xenografted mouse model indicated that Cle-NP was highly effective in tumor-specific degradation of endogenous Bcr-Abl expressed in K562 cells, leading to eventual tumor regression while maintaining good biosafety profiles. With key advantages of generality in molecular glue design, targeted delivery (e.g., H1-mGlu), potent antitumor activity partially induced by target-specific degradation, and minimized collateral damage to healthy tissues, our self-assembled nano-mGlu strategy thus provides a novel approach that might hold a significant promise for effective and personalized cancer therapy. |
| WOS关键词 | CHIMERAS PROTACS ; PROTEOLYSIS ; THALIDOMIDE ; INHIBITOR |
| 资助项目 | Science and Technology Foundation of Shenzhen City[2022YFA1104800] ; National Key R&D Program of China[JCYJ20210324124214038] ; Shenzhen Science and Technology Program[52072418] ; National Natural Science Foundation of China[23-0740-A0001] ; Changjiang Scholars Award Program of the Ministry of Education (China)[22-5025-A0001] ; Changjiang Scholars Award Program of the Ministry of Education (China)[T2EP10222-0002] ; Ministry of Education (MOE T1) |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001387532000001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315561]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Lu, Xiaoyun; Gao, Liqian; Yao, Shao Q.; Yuan, Peiyan |
| 作者单位 | 1.Cent South Univ, Xiangya Hosp, State Local Joint Engn Lab Anticanc Drugs, NHC Key Lab Canc Proteom,Dept Oncol, Changsha 410008, Hunan, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China 3.Jinan Univ, Sch Pharm, State Key Lab Bioact Mol & Druggabil Assessment, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Guangzhou 510632, Peoples R China 4.Natl Univ Singapore, Dept Chem, Singapore 117543, Singapore 5.Linyi Peoples Hosp, Dept Pharm, Linyi 276000, Peoples R China 6.Sun Yat Sen Univ, Sch Pharmaceut Sci Shenzhen, Shenzhen Campus, Shenzhen 518107, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Jie,Gu, Mingxi,Peng, Lvyang,et al. A Self-Assembled Nano-Molecular Glue (Nano-mGlu) Enables GSH/H2O2-Triggered Targeted Protein Degradation in Cancer Therapy[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2024,147(1):372-383. |
| APA | Sun, Jie.,Gu, Mingxi.,Peng, Lvyang.,Guo, Jing.,Chen, Peng.,...&Yuan, Peiyan.(2024).A Self-Assembled Nano-Molecular Glue (Nano-mGlu) Enables GSH/H2O2-Triggered Targeted Protein Degradation in Cancer Therapy.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(1),372-383. |
| MLA | Sun, Jie,et al."A Self-Assembled Nano-Molecular Glue (Nano-mGlu) Enables GSH/H2O2-Triggered Targeted Protein Degradation in Cancer Therapy".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.1(2024):372-383. |
入库方式： OAI收割
来源：上海药物研究所
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