The family of Bromodomain and Extra Terminal domain (BET) proteins are capable of binding to acetylated histone lysine residues to control DNA transcription. The BET proteins have two binding sites capable of recognizing acetylated lysine, sites 1 and 2. Researchers at St. Jude have discovered potent small molecule inhibitors that not only discriminate between BET family members, but can selectively prevent the binding of acetylated lysine to one binding domain in the presence of the other. The researchers propose that selective inhibition will lead to unique biological outcomes that current state of the art non-selective compounds will not.
These current pan-BET inhibitors (which block both BET binding domains with equal potency) have been linked to sterility and loss of cognitive function in mouse studies, likely due to the inability to discriminate between BET binding domains and family isoforms which control spermatogenesis. The new compounds selectively inhibit the second binding domain more strongly than the first binding domain in BET isoforms BRD2 and BRD4. They are also able to discriminate between family isoforms as well being less potent against BRD-T. This selectivity will lead to better outcomes when these compounds are administered, through higher potency, better tolerability, and fewer side effects than start of the art compounds.
We are seeking a partner who will license and help develop these inhibitors. At a minimum, these small molecules will benefit the research community by probing the effect of selective BET inhibition in biological contexts; and they also have the potential to be developed into novel pharmaceutical therapies for the treatment of cancer and inflammatory diseases.
Bromodomain and Extra Terminal domain (BET) proteins, DNA transcription, acetylated lysine, small molecule inhibitors, cancer and inflammatory diseases.
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