Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Abstract

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.

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

“…These clinical trials have been reviewed by Tang et al recently. [116] BETis reprogram pathological transcriptional program, triggering either cell death or cell cycle arrest in cancer. Preclinical studies have also revealed the beneficence of using BETi to treat seizures, [66] RTT, [107] inflammatory diseases and LPS-induced sepsis, [117] as well as mitochondrial diseases with Complex I mutations.…”

“…Inhibition of BRD4 leads to dysfunctions of the digestive system, fragile, hyperbilirubinemia, thrombocytopenia, anemia, metabolic disorders, and hyperglycemia. [116] Some of these impacts may be due to the vulnerability of normal proliferative cells to BETis. [122] Negative effects of BETis on the nervous system and immune system have not been reported, but they should be scrutinized in clinical trials as BRD4 is also essential in these systems.…”

Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis

“…The bromodomain and extraterminal (BET) family, including BRD2, BRD3, BRD4 and BRDT, can recognize N -acetyl lysine post-translational modifications on histone tails, each of which contains two conserved bromodomains named BD1 and BD2 1 , 2 , 3 . BD1 is mainly regarded as a chromatin-binding module and BD2 is typically used for transcription factor recruitment 4 , 5 .…”

“…There are over 40 clinical trials of BRD4 inhibition, most of them are used for malignant tumors and leukemia 3 , 10 , 11 , 12 . However, the occurrence of side effects, modest clinical efficacy and preclinical resistance have partly limited clinical application of BRD4 inhibitors 3 , 13 .…”

“…There are over 40 clinical trials of BRD4 inhibition, most of them are used for malignant tumors and leukemia 3 , 10 , 11 , 12 . However, the occurrence of side effects, modest clinical efficacy and preclinical resistance have partly limited clinical application of BRD4 inhibitors 3 , 13 . Therefore, there remains scope for the development of highly specific BRD4 inhibitors with alternative physicochemical, pharmacokinetic and pharmacodynamic profiles.…”