BET inhibitors are a class of drugs that reversibly bind the

bromodomain 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 transducin ...

s of Bromodomain and Extra-Terminal motif (BET) proteins

BRD2 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 Early descriptions dem ...

, BRD3,

BRD4 Bromodomain-containing protein 4 is a protein that in humans is encoded by the ''BRD4'' gene. BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET famil ...

, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.

Discovery and development

Thienodiazepine A thienodiazepine is a heterocyclic compound containing a diazepine ring fused to a thiophene Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extens ...

BET inhibitors were discovered by scientists at Yoshitomi Pharmaceuticals (now

Mitsubishi Tanabe Pharma Mitsubishi Tanabe Pharma Corporation is a Japanese pharmaceuticals company from Osaka, a subsidiary of Mitsubishi Chemical Holdings Corporation. was formed in 2001 from the merger of Mitsubishi-Tokyo Pharmaceuticals and Welfide Corporation. On ...

) in the early 1990s, and their potential both as anti-inflammatories and anti-cancer agents noted. However, these molecules remained largely unknown until 2010 when both the use of

JQ1 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 ...

NUT midline carcinoma NUT carcinoma (NC; formerly NUT midline carcinoma (NMC)) is a rare genetically defined, very aggressive squamous cell epithelial cancer that usually arises in the midline of the body and is characterized by a chromosomal rearrangement in the nucle ...

and of I-BET 762 in

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

were published. Since this time a number of molecules have been described that are capable of targeting BET bromodomains. 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). 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.

Mechanism of action

Interest in using BET inhibitors in cancer began with the observation that chromosomal translocations involving BET genes BRD3 and

drove the pathogenesis the rare cancer

. Subsequent research uncovered the dependence of some forms of

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...

and

acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...

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 ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...

is blocked by BET inhibitors. BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually. 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.

Specific BET inhibitors

BET inhibitors have been developed by publicly funded research labs as well as pharmaceutical companies including

GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...

, Oncoethix (purchased by Merck & Co. in 2014), Oncoethix, Constellation pharmaceuticals, Resverlogix Corp and Zenith epigenetics. Notable BET inhibitors include:

Targeting both BD1 and BD2 (bromodomains)

* I-BET 151 (GSK1210151A) * I-BET 762 ( GSK525762) * OTX-015 * TEN-010 * CPI-203 * CPI-0610

Selective targeting of BD1

* olinone, e.g. to affect the differentiation of

oligodendrocyte progenitor cell Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. ...

Selective targeting of BD2

* RVX-208 * ABBV-744

Dual kinase-bromodomain inhibitors

LY294002 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 ...

(some PI3K and BRD2, BRD3, and BRD4)

Bivalent BET inhibitors

* AZD5153 *MT-1 *MS645

References

{{Reflist, colwidth=35em Drugs blocking protein-protein interactions