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

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 BD2 s, 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Dysfunction of BET family proteins is associated with various human diseases, making them promising targets for drug development. Most current clinical BET inhibitors lack selectivity, but selective inhibitors targeting BD1 and BD2 are being developed to elucidate their distinct functions.