PROTACs in gastrointestinal cancers

Yu Chen; Qingfan Yang; Jinrun Xu; Liyao Tang; Yan Zhang; Fukuan Du; Yueshui Zhao; Xu Wu; Mingxing Li; Jing Shen; Ruilin Ding; Hongying Cao; Wanping Li; Xiaobing Li; Meijuan Chen; Zhigui Wu; Chi Hin Cho; Yu Du; Qinglian Wen; Zhangang Xiao

doi:10.1016/j.omto.2022.10.012

PROTACs in gastrointestinal cancers

Mol Ther Oncolytics. 2022 Nov 3:27:204-223. doi: 10.1016/j.omto.2022.10.012. eCollection 2022 Dec 15.

Authors

Yu Chen^{1

2}, Qingfan Yang³, Jinrun Xu^{1

2}, Liyao Tang^{1

2}, Yan Zhang^{1

2}, Fukuan Du^{1

2}, Yueshui Zhao^{1

2}, Xu Wu^{1

2}, Mingxing Li^{1

2}, Jing Shen^{1

2}, Ruilin Ding⁴, Hongying Cao⁵, Wanping Li^{1

2}, Xiaobing Li^{1

2}, Meijuan Chen^{1

2}, Zhigui Wu^{1

2}, Chi Hin Cho^{1

2}, Yu Du⁶, Qinglian Wen³, Zhangang Xiao^{3

7}

Affiliations

¹ Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
² South Sichuan Institute of Translational Medicine, Luzhou 646000, China.
³ Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646000, China.
⁴ Institute of Drug Clinical Trial/GCP Center, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646000, China.
⁵ Department of Emergency, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646000, China.
⁶ Medical Cosmetology Center, Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, Luzhou 646000, China.
⁷ Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Southwest Medical University, Luzhou 646000, China.

Abstract

Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.

Keywords: E3 ligases; PROTACs; cancer treatment; gastrointestinal cancers; targeted protein degradation.

Publication types

Review