Abstract
As epigenetic readers, the bromodomain and extra-terminal domain (BET) protein family binds to acetyl-lysine (KAc) residues and regulates chromatin structure and gene expression. Inhibition of BET proteins by small-molecule inhibitors for a variety of therapeutic applications has garnered increasing interest, as many compounds have advanced into human clinical trials for various diseases. The BET bromodomain family is composed of BRD2, BRD3, BRD4, and testis-specific BRDT. Knockout studies in mice have validated Brdt-1 as a potential target for male non-hormonal contraception, and the pan-BET inhibitor JQ1 was identified as an effective and reversible contraceptive. Numerous small-molecule compounds with potent inhibitory activity against BET family proteins have been reported. However, most of these inhibitors show minimal intra-BET selectivity due to high levels of sequence homology among the BET subfamily members and shared common structural architecture. Therefore, the discovery of selective small-molecule inhibitors against BRDT for male contraception remains a challenge for the future. This review will cover the structure and function of BRDT, known BRDT inhibitors and discuss potential approaches to discover selective BRDT inhibitors.
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