BET inhibitors are a class of drugs with anti-cancer, immunosuppressive, and other effects in clinical trials in the United States and Europe and widely used in research. These molecules 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 in cancer
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 RAF-inhibitor (vemurafenib) for RAF-inhibitor resistant melanomas carrying the BRAFV600E mutation.
Use in other applications
Pre-clinical studies have also demonstrated efficacy in applications that would require chronic administration (see below: heart failure and male contraception). As early studies in humans have already demonstrated significant toxicity in the form of thrombocytopenia, and these drugs are likely to have major immunomodulatory effects, it is unclear what the range of safe feasible applications for these molecules will be.
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)
- JQ1 – commonly used in research studies and distributed free of charge by the James Bradner laboratory at the Dana Farber Cancer Institute
- I-BET 151 (GSK1210151A) – widely used in research applications
- I-BET 762 (GSK525762) – in clinical trials evaluating safety and efficacy in patients with NUT midline carcinoma and hematologic malignancies
- OTX-015 – phase I trials results in patients with hematologic malignancies are available. Clinical trial testing conditions in patients with hematologic malignancies, solid tumors, glioblastoma multiforme, and NUT midline carcinoma
- TEN-010 – created by Tensha therapeutics
- CPI-203 – shown to be effective in multiple myeloma when given in combination with lenalidomide.
- CPI-0610 – currently being evaluated in phase I clinical trials for lymphoma, multiple myeloma, and other hematologic cancers.
Selective targeting of BD1
Dual kinase-bromodomain inhibitors
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