Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - A review

Chao-Yie Yang; Chong Qin; Longchuan Bai; Shaomeng Wang

doi:10.1016/j.ddtec.2019.04.001

Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - A review

Drug Discov Today Technol. 2019 Apr:31:43-51. doi: 10.1016/j.ddtec.2019.04.001. Epub 2019 May 1.

Authors

Chao-Yie Yang¹, Chong Qin¹, Longchuan Bai¹, Shaomeng Wang²

Affiliations

¹ The Rogel Cancer Center, Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States.
² The Rogel Cancer Center, Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: shaomeng@umich.edu.

PMID: 31200858
DOI: 10.1016/j.ddtec.2019.04.001

Abstract

The PROteolysis TArgeting Chimeric (PROTAC) concept has provided an opportunity for the discovery and development of a completely new type of therapy involving induction of protein degradation. The BET proteins, comprised of BRD2, BRD3, BRD4 and the testis-specific BRDT protein, are epigenetic readers and master transcription coactivators. Extremely potent and efficacious small-molecule PROTAC degraders of the BET proteins, based on available, potent and selective BET inhibitors, have been reported. BET degraders differ from BET inhibitors in their cellular potency, phenotypic effects, pharmacokinetic properties and toxicity profiles. Herein, we provide a review of BET degraders and the differential outcome observed in the cellular and animal models for BET degraders in comparison to BET inhibitors.

Publication types

Review

MeSH terms

Animals
Humans
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / metabolism*
Proteolysis
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism*

Substances

Nuclear Proteins
Transcription Factors