BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications

Abstract

The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists of four conserved members (Brd2, Brd3, Brd4, and Brdt) that regulate numerous cancer-related and immunity-associated genes. They are epigenetic readers of histone acetylation with broad specificity. BET proteins are linked to cancer progression due to their interaction with numerous cellular proteins including chromatin-modifying factors, transcription factors, and histone modification enzymes. The spectacular growth in the clinical development of small-molecule BET inhibitors underscores the interest and importance of this protein family as an anticancer target. Current approaches targeting BET proteins for cancer therapy rely on acetylation mimics to block the bromodomains from binding chromatin. However, bromodomain-targeted agents are suffering from dose-limiting toxicities because of their effects on other bromodomain-containing proteins. In this review, we provided an updated summary about the evolution of small-molecule BET inhibitors. The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed. The novel strategy of targeting the unique C-terminal extra-terminal (ET) domain of BET proteins and its therapeutic significance will also be highlighted. Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting.

Noval advance of histone modification in inflammatory skin diseases and related treatment methods

“…The most commonly observed treatment-related adverse events include thrombocytopenia, anemia, fatigue, and gastrointestinal complications ( 181 ). These side effects arise due to the ability of BET inhibitors to target any proteins containing bromodomains ( 182 ). Therefore, a BET inhibitor with enhanced selectivity and reduced side effects has been developed compared to pan BET inhibitors.…”

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress

“…Many experimental data have demonstrated that epigenetic drugs targeting BRDs exert protective effects on proliferative, inflammatory, and fibrotic diseases [29][30][31][32][33]. Different preclinical studies have demonstrated that the anti-inflammatory actions of JQ1 were mediated by the inhibition of the genetic expression of important proinflammatory factors [29][30][31]33].…”

“…Many experimental data have demonstrated that epigenetic drugs targeting BRDs exert protective effects on proliferative, inflammatory, and fibrotic diseases [29][30][31][32][33]. Different preclinical studies have demonstrated that the anti-inflammatory actions of JQ1 were mediated by the inhibition of the genetic expression of important proinflammatory factors [29][30][31]33]. The mechanism involved in the JQ1 anti-inflammatory action is mediated by the gene transcription inhibition through the blockade of the interaction of bromodomain, present in BET proteins, with acetylated lysine residues in proteins, including histones and transcription factors [29][30][31].…”

Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors

“…Recently, Wakita et al [ 87 ] studied the potential utilization of BET inhibitors/degraders as senolytics. Here, we are moving away from JQ1, which cannot be considered for clinical utilization due to unacceptably high levels of toxicity [ 88 , 89 , 90 ]. ARV-825 was shown to have potential senolytic activity using different senescence models, specifically human diploid fibroblasts (HDFs) driven into a senescent state via serial passage (replicative senescence), treatment with doxorubicin (therapy-induced senescence) and infection with a retrovirus encoding oncogenic Ras (+HRasV12) (oncogene-induced senescence).…”