BET inhibitors were discovered by scientists at Yoshitomi Pharmaceuticals 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. However, no BET inhibitor has yet been described that can reliably distinguish between BET family members. 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 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 factorMyc 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 for RAF-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, Oncoethix, Oncoethix, Constellation pharmaceuticals, Resverlogix Corp and Zenith epigenetics. Notable BET inhibitors include:
