The new direction of drug development: Degradation of undruggable targets through targeting chimera technology
文献类型：期刊论文
| 作者 | Liang, Xuewu4; Ren, Hairu3,4; Han, Fengyang2; Liang, Renwen4; Zhao, Jiayan3; Liu, Hong1,3,4
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| 刊名 | MEDICINAL RESEARCH REVIEWS
 |
| 出版日期 | 2023-11-20 |
| 页码 | 54 |
| ISSN号 | 0198-6325 |
| 关键词 | chimeric design degradation System PROTAC targeted degradation technology undruggable targets |
| DOI | 10.1002/med.21992 |
| 通讯作者 | Liu, Hong(hliu@simm.ac.cn) |
| 英文摘要 | Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin-proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand-binding pockets, about 80% of disease-associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology-related research advances and a new guidance for the chimeric design of undruggable targets. |
| WOS关键词 | SMALL-MOLECULE INHIBITOR ; PROTEIN-DEGRADATION ; TRANSCRIPTION FACTOR ; UBIQUITIN LIGASE ; CONFORMATIONAL DYNAMICS ; SELECTIVE DEGRADATION ; MEDIATED DEGRADATION ; ANDROGEN RECEPTOR ; STRUCTURAL BASIS ; HIGHLY POTENT |
| 资助项目 | This study was supported by the National Natural Science Foundation of China (21907102) and Lingang Laboratory (Grant nos. LG202103-02-07 and LG-QS-202205-09) for financial support.[21907102] ; National Natural Science Foundation of China[LG202103-02-07] ; National Natural Science Foundation of China[LG-QS-202205-09] ; Lingang Laboratory |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | WILEY |
| WOS记录号 | WOS:001104374200001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308122]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Liu, Hong |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Fudan Univ, Sch Pharm, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China 4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liang, Xuewu,Ren, Hairu,Han, Fengyang,et al. The new direction of drug development: Degradation of undruggable targets through targeting chimera technology[J]. MEDICINAL RESEARCH REVIEWS,2023:54. |
| APA | Liang, Xuewu,Ren, Hairu,Han, Fengyang,Liang, Renwen,Zhao, Jiayan,&Liu, Hong.(2023).The new direction of drug development: Degradation of undruggable targets through targeting chimera technology.MEDICINAL RESEARCH REVIEWS,54. |
| MLA | Liang, Xuewu,et al."The new direction of drug development: Degradation of undruggable targets through targeting chimera technology".MEDICINAL RESEARCH REVIEWS (2023):54. |
入库方式： OAI收割
来源：上海药物研究所
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