What are BET inhibitors?


BET inhibitor

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.

Discovery and development

Thienodiazepine BET inhibitors were discovered 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. However, these molecules remained largely unknown until 2010 when both the use of JQ1 in NUT midline carcinoma and of I-BET 762 in sepsis 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

BET inhibitors are a new class of anticancer drugs that scientists believe holds promise for treating blood cancers such as leukemia and lymphoma. BET inhibitors can inhibit tumor growth by blocking the function of BET proteins, and the BET protein family plays an important role in regulating gene expression.

BET inhibitors are effective in slowing tumor growth, but whether such drugs kill cancer cells completely or simply halt their growth has been unclear.

Interest in using BET inhibitors in cancer began with the observation that chromosomal translocations involving BET genes BRD3 and BRD4 drove the pathogenesis the rare cancer NUT midline carcinoma. Subsequent research uncovered the dependence of some forms of acute myeloid leukemia, multiple myeloma and acute lymphoblastic leukemia 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. 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.

The researchers said that when cancer cells lack the BIM protein, the apoptosis process will be damaged, and BET inhibitors will lose the effect of killing cancer cells, indicating that once cancer cells acquire genetic mutations that resist apoptosis, they will Loss of sensitivity to BET inhibitors, and therefore may survive drug treatment, leading to cancer recurrence.

An in-depth understanding of the mechanism of action of BET inhibitors can help researchers improve treatment strategies, such as using combination therapy or changing drug dosage and treatment duration, to prevent the emergence of drug resistance.

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), 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)

Selective targeting of BD1
olinone, e.g. to affect the differentiation of oligodendrocyte progenitor cells.: 4.1

Selective targeting of BD2

Dual kinase-bromodomain inhibitors
LY294002 (some PI3K and BRD2, BRD3, and BRD4)

Bivalent BET inhibitors

Source: Wiki