Bromodomain inhibitors and cancer therapy: From structures to applications

Abstract

Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…In many cell types, MYC is downregulated upon JQ1 treatment [3,42–44] and thought to be one of the key mediators of JQ1 effects. By contrast, MYC expression was found to be upregulated upon JQ1 treatment in H23 cells, suggesting that the effect of JQ1 treatment can vary depending on cancer or cell type, and, possibly, on genetic background.…”

“…Acetylated status of lysine residue is mainly recognized by bromodomains that are found in many chromatin-associated proteins [2,3]. The mammalian bromodomain and extra-terminal domain (BET) family, comprising BRD2, BRD3, BRD4, and BRDT, is involved in transcriptional regulation of cancer-related genes and has been recognized as a therapeutic target in many cancer types, such as NUT midline carcinoma (NMC) [4] and acute myeloid leukemia (AML) [5].…”

“…The mammalian bromodomain and extra-terminal domain (BET) family, comprising BRD2, BRD3, BRD4, and BRDT, is involved in transcriptional regulation of cancer-related genes and has been recognized as a therapeutic target in many cancer types, such as NUT midline carcinoma (NMC) [4] and acute myeloid leukemia (AML) [5]. JQ1, an inhibitor of BET proteins that binds the acetyllysine (Kac)-binding pocket of bromodomain [4], has been shown to selectively suppress the expression of tumor-promoting genes in cancer cells and emerges as a promising anti-cancer therapeutic drug [3,4,6–10]. Since studies on BET inhibition mechanisms have mostly focused on the correlation between BRD4 genomic occupancy and JQ1-induced transcriptional changes [6,11], little is known on how BRD2 and hyperacetylated histone H4, as the direct chromatin target of BET proteins, engage in the cancer-related pathways.…”

Emerging roles of and therapeutic strategies targeting BRD4 in cancer

“…Bromodomains are highly conserved domains that are made up of approximately 110 amino acids and are composed of a left-handed bundle of four alpha helices, which are linked by ZA and BC loops that vary in sequence between the bromodomain proteins. Despite variations in the ZA and BC loops, amino acid residues involved in acetyl lysine binding including asparagine (Asn) and tyrosine (Tyr) are conserved in bromodomains [3–6]. Bromodomain-containing proteins function as primary readers of acetylated lysine residues on the N- terminal tails of histones [7].…”

“…Sixty-one bromodomains (BrD) are present in the human genome representing eight subfamilies that classify members within the group. This review will focus on members belonging to subfamily II, the Bromo- and Extra-Terminal domain (BET) protein family [3–6]. …”