Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges

Shenxin Zeng; Wenhai Huang; Xiaoliang Zheng; Liyan Cheng; Zhimin Zhang; Jian Wang; Zhengrong Shen

doi:10.1016/j.ejmech.2020.112981

Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges

Eur J Med Chem. 2021 Jan 15:210:112981. doi: 10.1016/j.ejmech.2020.112981. Epub 2020 Oct 31.

Authors

Shenxin Zeng¹, Wenhai Huang¹, Xiaoliang Zheng², Liyan Cheng², Zhimin Zhang³, Jian Wang⁴, Zhengrong Shen⁵

Affiliations

¹ Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Hangzhou Medical College, Hangzhou, 310013, PR China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, PR China.
² Center for Molecular Medicine, Hangzhou Medical College, Hangzhou, 310013, PR China.
³ Department of Drug Platform of Small Molecules, HangZhou ZhongMei HuaDong Pharmaceutical CO, LTD, 866 Moganshan Road, Hangzhou, 310011, PR China.
⁴ School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, PR China.
⁵ Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Hangzhou Medical College, Hangzhou, 310013, PR China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, PR China. Electronic address: Shenzr601@163.com.

PMID: 33160761
DOI: 10.1016/j.ejmech.2020.112981

Abstract

Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and recruiting E3 ligase for target degradation via the ubiquitin-proteasome pathway, is a novel drug discovery paradigm which has been widely used as biological tools and medicinal molecules with the potential of clinical application value. Currently, ARV-110, an orally small molecule PROTAC was designed to specifically target Androgen receptor (AR), firstly enters clinical phase I trials for the treatment of metastatic castration-resistant prostate cancer, which turns a new avenue for the development of PROTAC. We herein provide a detail summary on the latest one year progress of PROTAC target various proteins and elucidate the advantages of PROTAC technology. Finally, the potential challenges of this vibrant field are also discussed.

Keywords: Drug discovery; Drug resistance; PROTAC; Small molecule; Target protein degradation; Undruggable target.

Publication types

Review

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Proteolysis / drug effects
Receptors, Androgen / metabolism*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

AR protein, human
Receptors, Androgen
Small Molecule Libraries