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Accelerating PROTACs Discovery Through a Direct-to-Biology Platform Enabled by Modular Photoclick Chemistry

文献类型：期刊论文

作者Yan, Ke-Nian4,5; Nie, Yong-Qiang3; Wang, Jia-Yu2; Yin, Guang-Liang4,5; Liu, Qia1,4; Hu, Hao5; Sun, Xiaoxia3; Chen, Xiao-Hua1,2,4,5
刊名ADVANCED SCIENCE
出版日期2024-04-30
页码12
关键词High-throughput chemical synthesis modular synthesis photoclick chemistry PROTACs library targeted protein degradation
DOI10.1002/advs.202400594
通讯作者Sun, Xiaoxia(xxsun@jxstnu.edu.cn) ; Chen, Xiao-Hua(xhchen@simm.ac.cn)
英文摘要Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering a revolutionary therapeutic modality. Currently, the predominant approach to PROTACs discovery mainly relies on an empirical design-synthesis-evaluation process involving numerous cycles of labor-intensive synthesis-purification and bioassay data collection. Therefore, the development of innovative methods to expedite PROTAC synthesis and exploration of chemical space remains highly desired. Here, a direct-to-biology strategy is reported to streamline the synthesis of PROTAC libraries on plates, enabling the seamless transfer of reaction products to cell-based bioassays without the need for additional purification. By integrating amide coupling and light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into a plate-based synthetic process, this strategy produces PROTAC libraries with high efficiency and structural diversity. Moreover, by employing this platform for PROTACs screening, we smoothly found potent PROTACs effectively inhibit triple-negative breast cancer (TNBC) cell growth and induce rapid, selective targeted degradation of cyclin-dependent kinase 9 (CDK9). The study introduces a versatile platform for assembling PROTACs on plates, followed by direct biological evaluation. This approach provides a promising opportunity for high-throughput synthesis of PROTAC libraries, thereby enhancing the efficiency of exploring chemical space and accelerating the discovery of PROTACs. A direct-to-biology platform has been established to streamline proteolysis targeting chimeras (PROTACs) library synthesis in plate, via integrating amide coupling and light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry, allowing seamless transfer for immediate cell-based evaluation. This approach enables rapid discovery of potent cyclin-dependent kinase 9-targeting PROTACs. The platform enhances efficiency in chemical space exploration, accelerating PROTAC discovery. image
WOS关键词PROTEINS
资助项目National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality[21S11900700] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0220233001] ; [22377136] ; [22377133]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001210459700001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/310861]  
专题新药研究国家重点实验室
通讯作者Sun, Xiaoxia; Chen, Xiao-Hua
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Jiangxi Sci & Technol Normal Univ, Jiangxi Key Lab Organ Chem, Nanchang 330013, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Ke-Nian,Nie, Yong-Qiang,Wang, Jia-Yu,et al. Accelerating PROTACs Discovery Through a Direct-to-Biology Platform Enabled by Modular Photoclick Chemistry[J]. ADVANCED SCIENCE,2024:12.
APA Yan, Ke-Nian.,Nie, Yong-Qiang.,Wang, Jia-Yu.,Yin, Guang-Liang.,Liu, Qia.,...&Chen, Xiao-Hua.(2024).Accelerating PROTACs Discovery Through a Direct-to-Biology Platform Enabled by Modular Photoclick Chemistry.ADVANCED SCIENCE,12.
MLA Yan, Ke-Nian,et al."Accelerating PROTACs Discovery Through a Direct-to-Biology Platform Enabled by Modular Photoclick Chemistry".ADVANCED SCIENCE (2024):12.

入库方式： OAI收割

来源：上海药物研究所

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