Progress in the development of domain selective inhibitors of the bromo and extra terminal domain family (BET) proteins

Yuantao Fu; Yanzhi Zhang; Haiying Sun

doi:10.1016/j.ejmech.2021.113853

Progress in the development of domain selective inhibitors of the bromo and extra terminal domain family (BET) proteins

Eur J Med Chem. 2021 Dec 15:226:113853. doi: 10.1016/j.ejmech.2021.113853. Epub 2021 Sep 13.

Authors

Yuantao Fu¹, Yanzhi Zhang¹, Haiying Sun²

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
² Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: haiyings1969@cpu.edu.cn.

PMID: 34547507
DOI: 10.1016/j.ejmech.2021.113853

Abstract

Dysfunction of the bromo and extra terminal domain (BET) family proteins is associated with many human diseases, therefore the BET family proteins have been considered as promising targets for drug development. Numerous small molecular compounds targeting the N-terminal two tandem bromodomains BD1 and BD2 of the BET family proteins have been reported, and a number of them have been advanced into clinical trials. Most of the BET inhibitors entered clinical trials are pan-BET inhibitors which show poor selectivity among BET members and bind to the BD1 and BD2 of the BET family proteins with comparable binding affinities. In order to elucidate the distinct functions of BD1s and BD2s, many BD1 and BD2 selective BET inhibitors have also been developed. In this review, we summarized the recent progress in the development of BD1 and BD2 selective BET inhibitors, and provided the perspectives for future studies of BET inhibitors.

Keywords: BET; Bromodomain; Cancer; Epigenetic; Transcription.

Publication types

Review

MeSH terms

Azepines / chemical synthesis
Azepines / chemistry
Azepines / pharmacology*
Drug Development*
Humans
Molecular Structure
Protein Domains / drug effects
Proteins / antagonists & inhibitors*
Proteins / chemistry
Proteins / metabolism
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

(+)-JQ1 compound
Azepines
Proteins
Triazoles
bromodomain and extra-terminal domain protein, human