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PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders

文献类型：期刊论文

作者Chen, Shuqiang3; Bi, Kaijian3; Liang, Huixin3; Wu, Zhe3; Huang, Min2; Chen, Xi1; Dong, Guoqiang3; Sheng, Chunquan3
刊名JOURNAL OF ADVANCED RESEARCH
出版日期2024-09-01
卷号63页码:219-230
关键词PROTAC Natural products Target identification Quantitative proteomics Antitumor activities
ISSN号2090-1232
DOI10.1016/j.jare.2023.10.014
通讯作者Chen, Shuqiang(chenshuq1992@163.com) ; Sheng, Chunquan(shengcq@smmu.edu.cn)
英文摘要Introduction: Natural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. Objectives: Inspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. Methods: Taking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. Results: In this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo, , leading to potent antitumor activities and reduced toxic side effects. Conclusion: In summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
WOS关键词CHIMERIC MOLECULES ; HIGHLY POTENT ; DERIVATIVES ; AGENTS ; DAMAGE ; HPMC2
资助项目National Natural Science Foundation of China[22007099] ; National Natural Science Foundation of China[82030105] ; National Key Research and Development Program of China[2022YFC3401500] ; Shanghai sailing program[20YF1458600]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001298101000001
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/313068]  
专题新药研究国家重点实验室
通讯作者Chen, Shuqiang; Sheng, Chunquan
作者单位1.Northwest Univ, Coll Chem & Mat Sci, Key Lab Synthet & Nat Funct Mol, Minist Educ, Xian 710127, Peoples R China
2.Univ Chinese Acad Sci, Shanghai Inst Mat Med, Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Naval Med Univ, Mil Med Univ 2, Ctr Basic Res & Innovat Med & Pharm MOE, Sch Pharm, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Shuqiang,Bi, Kaijian,Liang, Huixin,et al. PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders[J]. JOURNAL OF ADVANCED RESEARCH,2024,63:219-230.
APA Chen, Shuqiang.,Bi, Kaijian.,Liang, Huixin.,Wu, Zhe.,Huang, Min.,...&Sheng, Chunquan.(2024).PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders.JOURNAL OF ADVANCED RESEARCH,63,219-230.
MLA Chen, Shuqiang,et al."PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders".JOURNAL OF ADVANCED RESEARCH 63(2024):219-230.

入库方式： OAI收割

来源：上海药物研究所

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