E3 ligase ligand optimization of Clinical PROTACs

Hanrui Jiang; Huan Xiong; Shuang-Xi Gu; Mingliang Wang

doi:10.3389/fchem.2023.1098331

E3 ligase ligand optimization of Clinical PROTACs

Front Chem. 2023 Jan 17:11:1098331. doi: 10.3389/fchem.2023.1098331. eCollection 2023.

Authors

Hanrui Jiang^{1

2}, Huan Xiong^{2

3}, Shuang-Xi Gu¹, Mingliang Wang^{2

3}

Affiliations

¹ Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, China.
² Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
³ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Abstract

Proteolysis targeting chimeras (PROTACs) technology can realize the development of drugs for non-druggable targets that are difficult to achieve with traditional small molecules, and therefore has attracted extensive attention from both academia and industry. Up to now, there are more than 600 known E3 ubiquitin ligases with different structures and functions, but only a few have developed corresponding E3 ubiquitin ligase ligands, and the ligands used to design PROTAC molecules are limited to a few types such as VHL (Von-Hippel-Lindau), CRBN (Cereblon), MDM2 (Mouse Doubleminute 2 homolog), IAP (Inhibitor of apoptosis proteins), etc. Most of the PROTAC molecules that have entered clinical trials were developed based on CRBN ligands, and only DT2216 was based on VHL ligand. Obviously, the structural optimization of E3 ubiquitin ligase ligands plays an instrumental role in PROTAC technology from bench to bedside. In this review, we review the structure optimization process of E3 ubiquitin ligase ligands currently entering clinical trials on PROTAC molecules, summarize some characteristics of these ligands in terms of druggability, and provide some preliminary insights into their structural optimization. We hope that this review will help medicinal chemists to develop more druggable molecules into clinical studies and to realize the greater therapeutic potential of PROTAC technology.

Keywords: CRBN; E3 ubiquitin ligase ligand; PROTACs; clinical trials; structure optimization.

Publication types

Review

Grants and funding

This work was supported by Highlevel new R&D institute (2019B090904008), and High-level Innovative Research Institute (2021B0909050003) from Department of Science and Technology of Guangdong Province.