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

Shuqiang Chen; Kaijian Bi; Huixin Liang; Zhe Wu; Min Huang; Xi Chen; Guoqiang Dong; Chunquan Sheng

doi:10.1016/j.jare.2023.10.014

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

J Adv Res. 2023 Oct 31:S2090-1232(23)00318-1. doi: 10.1016/j.jare.2023.10.014. Online ahead of print.

Authors

Shuqiang Chen¹, Kaijian Bi², Huixin Liang², Zhe Wu², Min Huang³, Xi Chen⁴, Guoqiang Dong², Chunquan Sheng⁵

Affiliations

¹ The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, People's Republic of China. Electronic address: chenshuq1992@163.com.
² The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, People's Republic of China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
⁴ Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, People's Republic of China.
⁵ The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, People's Republic of China. Electronic address: shengcq@smmu.edu.cn.

PMID: 37913903
DOI: 10.1016/j.jare.2023.10.014

Abstract

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-10-hydroxylevodiamine, 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.

Keywords: Antitumor activities; Natural products; PROTAC; Quantitative proteomics; Target identification.