Key Considerations in Targeted Protein Degradation Drug Discovery and Development
文献类型：期刊论文
| 作者 | Qin, Liena4; Dai, Han3; Wang, Junfeng1,2,3 |
| 刊名 | FRONTIERS IN CHEMISTRY
 |
| 出版日期 | 2022-08-01 |
| 卷号 | 10 |
| ISSN号 | 2296-2646 |
| 关键词 | targeted protein degradation PROTAC molecular glue chemically induced proximity drug discovery and development |
| DOI | 10.3389/fchem.2022.934337 |
| 通讯作者 | Qin, Liena(liena.qin@insilico.ai) ; Dai, Han(daihan@hmfl.ac.cn) ; Wang, Junfeng(junfeng@hmfl.ac.cn) |
| 英文摘要 | Targeting proteins' enzymatic functions with small molecule inhibitors, as well as functions of receptor proteins with small-molecule agonists and antagonists, were the major forms of small-molecule drug development. These small-molecule modulators are based on a conventional occupancy-driven pharmacological approach. For proteome space traditionally considered undruggable by small-molecule modulators, such as enzymes with scaffolding functions, transcription factors, and proteins that lack well-defined binding pockets for small molecules, targeted protein degraders offer the opportunity to drug the proteome with an event-driven pharmacological approach. A degrader molecule, either PROTAC or molecular glue, brings the protein of interest (POI) and E3 ubiquitin ligase in close proximity and engages the ubiquitin-proteasome system (UPS), the cellular waste disposal system for the degradation of the POI. For the development of targeted protein degraders to meet therapeutic needs, several aspects will be considered, namely, the selective degradation of disease-causing proteins, the oral bioavailability of degraders beyond Lipinski's rule of five (bRo5) scope, demands of new E3 ubiquitin ligases and molecular glue degraders, and drug resistance of the new drug modality. This review will illustrate several under-discussed key considerations in targeted protein degradation drug discovery and development: 1) the contributing factors for the selectivity of PROTAC molecules and the design of PROTACs to selectively degrade synergistic pathological proteins; 2) assay development in combination with a multi-omics approach for the identification of new E3 ligases and their corresponding ligands, as well as molecular glue degraders; 3) a molecular design to improve the oral bioavailability of bRo5 PROTACs, and 4) drug resistance of degraders. |
| WOS关键词 | E3 UBIQUITIN LIGASES ; SELECTIVE DEGRADATION ; STRUCTURAL BASIS ; SMALL MOLECULES ; PROTAC DESIGN ; IDENTIFICATION ; RESISTANCE ; INHIBITION ; DEGRADERS ; INDUCERS |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| 出版者 | FRONTIERS MEDIA SA |
| WOS记录号 | WOS:000840769200001 |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/132031]  |
| 专题 | 中国科学院合肥物质科学研究院 |
| 通讯作者 | Qin, Liena; Dai, Han; Wang, Junfeng |
| 作者单位 | 1.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei, Peoples R China 2.Int Magnetobiol Frontier Res Ctr, Hefei, Peoples R China 3.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, CAS Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei, Peoples R China 4.Insilico Med Ltd, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Qin, Liena,Dai, Han,Wang, Junfeng. Key Considerations in Targeted Protein Degradation Drug Discovery and Development[J]. FRONTIERS IN CHEMISTRY,2022,10. |
| APA | Qin, Liena,Dai, Han,&Wang, Junfeng.(2022).Key Considerations in Targeted Protein Degradation Drug Discovery and Development.FRONTIERS IN CHEMISTRY,10. |
| MLA | Qin, Liena,et al."Key Considerations in Targeted Protein Degradation Drug Discovery and Development".FRONTIERS IN CHEMISTRY 10(2022). |
入库方式： OAI收割
来源：合肥物质科学研究院
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。