Bromodomain
and extraterminal (BET) proteins bind acetylated lysine
residues in histones and nonhistone proteins via tandem bromodomains
and regulate chromatin dynamics, cellular processes, and disease procession.
Thus targeting BET proteins is a promising strategy for treating various
diseases, especially malignant tumors and chronic inflammation. Many
pan-BET small-molecule inhibitors have been described, and some of
them are in clinical evaluation. Nevertheless, the limited clinical
efficacy of the current BET inhibitors is also evident and has inspired
the development of new technologies to improve their clinical outcomes
and minimize unwanted side effects. In this Review, we summarize the
latest protein characteristics and biological functions of BRD4 as
an example of BET proteins, analyze the clinical development status
and preclinical resistance mechanisms, and discuss recent advances
in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis
targeting chimera degraders, and protein–protein interaction
inhibitors.
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