Recent progress and structural analyses of domain-selective BET inhibitors

卷:43

Review

关键词: BROMODOMAIN PROTEIN BRD4;    NF-KAPPA-B;    HOLE APPROACH;    1ST BROMODOMAIN;    SMALL-MOLECULE;    P-TEFB;    OPTIMIZATION;    CHROMATIN;    POTENT;    BROMO;   

DOI  :  10.1002/med.21942

来源: SCIE

【 摘 要 】

Epigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine-epsilon-N-acetylation (K-ac), bromodomains serve as recognition modules (readers) of this activating epigenetic mark and competition of the bromodomain-K-ac interaction with small-molecule inhibitors is an attractive strategy to control aberrant bromodomain-mediated gene expression. The bromodomain and extra-terminal (BET) family proteins contain eight similar bromodomains. These BET bromodomains are among the more commonly studied bromodomain classes with numerous pan-BET inhibitors showing promising anticancer and anti-inflammatory efficacy. However, these results have yet to translate into Food and Drug Administration-approved drugs, in part due to a high degree of on-target toxicities associated with pan-BET inhibition. Improved selectivity within the BET-family has been proposed to alleviate these concerns. In this review, we analyze the reported BET-domain selective inhibitors from a structural perspective. We highlight three essential characteristics of the reported molecules in generating domain selectivity, binding affinity, and mimicking K-ac molecular recognition. In several cases, we provide insight into the design of molecules with improved specificity for individual BET-bromodomains. This review provides a perspective on the current state of the field as this exciting class of inhibitors continue to be evaluated in the clinic.

【 授权许可】

Free