BET inhibitor

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BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors. [1] [2]

Contents

Discovery and development

Thienodiazepine BET inhibitors were discovered in a phenotypic drug screen by scientists at Yoshitomi Pharmaceuticals (now Mitsubishi Tanabe Pharma) in the early 1990s, and their potential both as anti-inflammatories and anti-cancer agents noted. [3] [4] OncoEthix (acquired by Merck in 2014) in-licensed OTX-015 from Mitsubishi and in 2012 initiated the first BET inhibitor clinical trial for oncology (ClinicalTrials.gov Identifier: NCT01713582). BET inhibitors were also independently discovered in phenotypic screens for small molecule inducers of Apolipoprotein A-I by both GSK and Resverlogix. [5] [6] In 2010 the use of JQ1, a tert-butyl synthetic precursor of OTX-015, was published having activity in vitro in NUT midline carcinoma. [7] Since this time a number of molecules have been described that are capable of targeting BET bromodomains. [8]

BET inhibitors have been described that are able to discriminate between the first and second bromodomains of BET proteins (BD1 vs BD2). However, no BET inhibitor has yet been described that can reliably distinguish between BET family members (BRD2 vs BRD3 vs BRD4 vs BRDT). [9] Only in the research context has targeting individual BET proteins been achieved by mutating them to be more sensitive to a derivative of JQ1 / I-BET 762. [10]

Mechanism of action

Interest in using BET inhibitors in cancer began with the observation that chromosomal translocations involving BET genes BRD3 and BRD4 drove the pathogenesis of the rare cancer NUT midline carcinoma. Subsequent research uncovered the dependence of some forms of acute myeloid leukemia, [11] [12] multiple myeloma and acute lymphoblastic leukemia [13] on the BET protein BRD4, and the sensitivity of these cancers to BET inhibitors. In many cases, expression of the growth promoting transcription factor Myc is blocked by BET inhibitors. [14] [15] [16] BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually. [17] Recent studies also showed that BET inhibitors can be instrumental in overcoming resistance to other targeted therapies when used in combination therapies. Examples include use of BET inhibitors in combination with γ-secretase inhibitors for T cell acute lymphoblastic leukemia and BRAF-inhibitor (vemurafenib) for BRAF-inhibitor resistant melanomas carrying the BRAFV600E mutation. [18] [19]

Specific BET inhibitors

BET inhibitors have been developed by publicly funded research labs as well as pharmaceutical companies including GlaxoSmithKline, Oncoethix (purchased by Merck & Co. in 2014 [20] ), Oncoethix, [21] Constellation pharmaceuticals, [22] Resverlogix Corp [23] and Zenith epigenetics. [24] Notable BET inhibitors include:

Targeting both BD1 and BD2 (bromodomains)

Selective targeting of BD1

Selective targeting of BD2

Dual kinase-bromodomain inhibitors

Bivalent BET inhibitors

See also

Related Research Articles

<span class="mw-page-title-main">Bromodomain</span>

A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.

The Structural Genomics Consortium (SGC) is a public-private-partnership focusing on elucidating the functions and disease relevance of all proteins encoded by the human genome, with an emphasis on those that are relatively understudied. The SGC places all its research output into the public domain without restriction and does not file for patents and continues to promote open science. Two recent publications revisit the case for open science. Founded in 2003, and modelled after the Single Nucleotide Polymorphism Database (dbSNP) Consortium, the SGC is a charitable company whose Members comprise organizations that contribute over $5,4M Euros to the SGC over a five-year period. The Board has one representative from each Member and an independent Chair, who serves one 5-year term. The current Chair is Anke Müller-Fahrnow (Germany), and previous Chairs have been Michael Morgan (U.K.), Wayne Hendrickson (U.S.A.), Markus Gruetter (Switzerland) and Tetsuyuki Maruyama (Japan). The founding and current CEO is Aled Edwards (Canada). The founding Members of the SGC Company were the Canadian Institutes of Health Research, Genome Canada, the Ontario Research Fund, GlaxoSmithKline and Wellcome Trust. The current Members comprise Bayer Pharma AG, Bristol Myers Squibb, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, Pfizer, and Takeda.

<span class="mw-page-title-main">BRD2</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 2 is a protein that in humans is encoded by the BRD2 gene. BRD2 is part of the Bromodomain and Extra-Terminal motif (BET) protein family that also contains BRD3, BRD4, and BRDT in mammals

<span class="mw-page-title-main">BRD4</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.

<span class="mw-page-title-main">BRD7</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 7 is a protein that in humans is encoded by the BRD7 gene.

<span class="mw-page-title-main">Bromodomain-containing protein 3</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 3 (BRD3) also known as RING3-like protein (RING3L) is a protein that in humans is encoded by the BRD3 gene. This gene was identified based on its homology to the gene encoding the RING3 (BRD2) protein, a serine/threonine kinase. The gene maps to 9q34, a region which contains several major histocompatibility complex (MHC) genes.

<span class="mw-page-title-main">LY294002</span> Chemical compound

LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used for experiments aiming to target PI3K uniquely.

<span class="mw-page-title-main">BRDT</span> Protein-coding gene in the species Homo sapiens

Bromodomain testis-specific protein is a protein that in humans is encoded by the BRDT gene. It is a member of the Bromodomain and Extra-terminal motif (BET) protein family.

<span class="mw-page-title-main">Ming-Ming Zhou</span>

Ming-Ming Zhou is an American scientist who focuses on structural and chemical biology, NMR spectroscopy, and drug design. He is the Dr. Harold and Golden Lamport Professor and Chairman of the Department of Pharmacological Sciences. He is also the co-director of the Drug Discovery Institute at the Icahn School of Medicine at Mount Sinai and Mount Sinai Health System in New York City, as well as Professor of Sciences. Zhou is an elected fellow of the American Association for the Advancement of Science.

<span class="mw-page-title-main">JQ1</span> Chemical compound

JQ1 is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain proteins which include BRD2, BRD3, BRD4, and the testis-specific protein BRDT in mammals. BET inhibitors structurally similar to JQ1 are being tested in clinical trials for a variety of cancers including NUT midline carcinoma. It was developed by the James Bradner laboratory at Brigham and Women's Hospital and named after chemist Jun Qi. The chemical structure was inspired by patent of similar BET inhibitors by Mitsubishi Tanabe Pharma [WO/2009/084693]. Structurally it is related to benzodiazepines. While widely used in laboratory applications, JQ1 is not itself being used in human clinical trials because it has a short half life.

Chem-seq is a technique that is used to map genome-wide interactions between small molecules and their protein targets in the chromatin of eukaryotic cell nuclei. The method employs chemical affinity capture coupled with massively parallel DNA sequencing to identify genomic sites where small molecules interact with their target proteins or DNA. It was first described by Lars Anders et al. in the January, 2014 issue of "Nature Biotechnology".

<span class="mw-page-title-main">Apabetalone</span> Chemical compound

Apabetalone is an orally available small molecule created by Resverlogix Corp. that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD). In the phase II clinical trial ASSURE in patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels, apabetalone showed no greater increase in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels or incremental regression of atherosclerosis than administration of placebo, while causing a statistically significant greater incidence of elevated liver enzymes. However, pooled analysis of the effect of apabetalone in three phase II clinical trials ASSERT, ASSURE, and SUSTAIN demonstrated increases in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreases in the incidence of major adverse cardiac events (MACE). Reduction of MACE was more profound in patients with diabetes mellitus. In a short-term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone. An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015. The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.

AI-10-49 is a small molecule inhibitor of leukemic oncoprotein CBFβ-SMHHC developed by the laboratory of John Bushweller with efficacy demonstrated by the laboratories of Lucio H. Castilla and Monica Guzman. AI-10-49 allosterically binds to CBFβ-SMMHC and disrupts protein-protein interaction between CBFβ-SMMHC and tumor suppressor RUNX1. This inhibitor is under development as an anti-leukemic drug.

Bromodomain-containing protein 9 is a protein that in humans is encoded by the BRD9 gene.

In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity. Because super-enhancers are frequently identified near genes important for controlling and defining cell identity, they may thus be used to quickly identify key nodes regulating cell identity.

A proteolysis targeting chimera (PROTAC) is a heterobifunctional molecule composed of two active domains and a linker, capable of removing specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity, there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.

<span class="mw-page-title-main">Transcriptional amplification</span>

In genetics, transcriptional amplification is the process in which the total amount of messenger RNA (mRNA) molecules from expressed genes is increased during disease, development, or in response to stimuli.

<span class="mw-page-title-main">CPI-0610</span> Chemical compound

CPI-0610 is a drug which acts as a BET inhibitor, mainly acting at the BRD2 and BRD4 subtypes. It has potential applications in the treatment of various forms of cancer.

<span class="mw-page-title-main">Bump and hole</span>

The bump-and-hole method is a tool in chemical genetics for studying a specific isoform in a protein family without perturbing the other members of the family. The unattainability of isoform-selective inhibition due to structural homology in protein families is a major challenge of chemical genetics. With the bump-and-hole approach, a protein–ligand interface is engineered to achieve selectivity through steric complementarity while maintaining biochemical competence and orthogonality to the wild type pair. Typically, a "bumped" ligand/inhibitor analog is designed to bind a corresponding "hole-modified" protein. Bumped ligands are commonly bulkier derivatives of a cofactor of the target protein. Hole-modified proteins are recombinantly expressed with an amino acid substitution from a larger to smaller residue, e.g. glycine or alanine, at the cofactor binding site. The designed ligand/inhibitor has specificity for the engineered protein due to steric complementarity, but not the native counterpart due to steric interference.

The nuclear protein in testis gene encodes a 1,132-amino acid protein termed NUT that is expressed almost exclusively in the testes, ovaries, and ciliary ganglion. NUT protein facilitates the acetylation of chromatin by histone acetyltransferase EP300 in testicular spermatids. This acetylation is a form of chromatin remodeling which compacts spermatid chromatin, a critical step required for the normal conduct of spermatogenesis, i.e. the maturation of spermatids into sperm. Male mice that lacked the mouse Nutm1 gene using a gene knockout method had abnormally small testes, lacked sperm in their cauda epididymis, and were completely sterile. These findings indicate that Nutm1 gene is essential for the development of normal fertility in male mice and suggest that the NUTM1 gene may play a similar role in men.

References

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  41. ↑ Ren C, Zhang G, Han F, Fu S, Cao Y, Zhang F, Zhang Q, Meslamani J, Xu Y, Ji D, Cao L, Zhou Q, Cheung KL, Sharma R, Babault N, Yi Z, Zhang W, Walsh MJ, Zeng L, Zhou MM (July 2018). "Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth". Proceedings of the National Academy of Sciences of the United States of America. 115 (31): 7949–7954. doi: 10.1073/pnas.1720000115 . PMC   6077712 . PMID   30012592.
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