Small molecule inhibitors of BET proteins: opportunities and possible pitfalls

Using a targeted epigenetic approach, our lab has shown that it is possible to uncouple obesity from inflammation and diabetes. Our animal studies have produced severely obese mice that are metabolically healthy, have a reduced inflammatory profile and are protected from Type 2 diabetes (mice die of old age). This epigenetic approach involves a family of regulatory proteins called double bromodomain proteins (BET) that bind to acetylated lysines in histones and control gene expression. We are specifically targeting one BET family member, Brd2. We plan to create novel derivatives of a BET inhibitor tool compound that will selectively inhibit Brd2.

We are discoverers of the BET family of proteins and have pioneered the pathway biology in cancer and now metabolism and inflammation. There are important areas of unmet medical need that could benefit from epigenetic drugs, such as small molecule inhibitors of BET proteins. For example, selective Brd2 inhibitors may be usesful to treat acute and chronic inflammatory diseases including obesity-associated Type 2 diabetes and β-cell failure, i.e. Type 1 diabetes.

Belkina et al 2013 – JI

Possible pitfalls: Any immunosuppressive approach runs the risk of complications, including lymphoma (e.g. high dose cyclosporin after organ transplant) or opportunistic infection. These problems could be dealt with in humans by: 1. calibration of the dose to achieve efficacy (i.e. reduced serum TNF) without total ablation, or 2. acute administration to ‘reset’ inflammation at a lower level, then taper the dose.

More seriously, BET inhibitors might derepress transcription of endogenous human retroviruses or other latent DNA viruses in the genome, because the BET protein-containing transcriptional co-regulator complexes also perform co-repressor functions, not just co-activator functions, depending on the demands of the specific promoter, signal transduction and cell type. Thus there are significant, unexplored risks to the strategy of treating humans systemically with small molecule BET inhibitors. These concerns, which must be addressed before clinical trials can proceed safely, are outlined in detail in the 2012 Nature Reviews Cancer article appended below.

Belkina and Denis, 2012

Alternatively, virus reactivation may be a highly useful strategy for eradication of HIV from infected human T-cells, as we have recently shown in collaboration with the laboratory of Monty Montano at Boston University Medical Center.

Banerjee et al 2012

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