Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

Abstract

Clinical development of bromodomain and extra‐terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic “readers,” which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan‐BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.

Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer

“…Undoubtedly, the indirect approach to regulating MYC that has gained most attention in recent years is a class of drugs that can target the bromodomains of the bromodomain and extraterminal (BET) proteins BRD2, 3 and 4 ( Figure 3 ). These compounds inhibit association of the BET proteins with acetylated histones on active chromatin, preventing recruitment of transcription factors and, thereby, blocking transcription of target genes, most notably, MYC [ 277 , 278 ]. Since the first BET inhibitor (BETi) JQ1 was reported, a number of other similar compounds have been developed, including some that are specific for particular bromodomains, bivalent BETi and BETi associated with proteolysis-targeting (i.e., PROTACs) moieties [ 279 , 280 , 281 , 282 , 283 , 284 ].…”

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

“…Drugs are designed on the basis of mimicking the acetyl-lysine group to act as competitors for binding of BET proteins to the chromatin. New strategies like proteolytic targeting chimeras (PROTAC) have recently enriched the therapeutic landscape devoted not only to fight cancer and inflammation but cardiovascular, metabolic, viral and neurological diseases [reviewed in (Andrieu et al, 2018;Singh and Sartor, 2020;Kulikowski et al, 2021)]. Interestingly, BRD2 and BRD4 have been also linked to juvenile myoclonic epilepsy and to learning and memory, respectively (Velisek et al, 2011;Korb et al, 2015).…”

“…These elements are very relevant in the maintenance of cell identity and in cancer transformation, regulating the expression of oncogenes on which cancer cells become highly dependent (Di Micco et al, 2014;Shi and Vakoc, 2014). An additional term, and potentially closely linked to disease, is latent enhancers, defined as regions in terminally differentiated cells deployed of typical proteins and marks associated with enhancers, but able to acquire them in response to certain stimuli (Ostuni et al, 2013;Kulikowski et al, 2021). They share many characteristics with SEs, and many of them do not return to the basal state once the stimulus ceases, but remain in a memory-mediated latent state for faster and greater induction upon subsequent stimulation.…”

7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth

“…It can recognize and bind histone and non-histone acetylated lysine to participate in the development of many diseases ( Moriniere et al, 2009 ). Recent reports indicating that BRD4 is highly expressed in various cancers, including gastric cancer, breast cancer, leukemia and so on ( Sahai et al, 2016 ; Kulikowski et al, 2021 ), and is involved in regulating cell growth, cell cycle and apoptosis, and other cell processes. Its imbalance is related to the occurrence and development of many cancers.…”