Selective disruption of histone deacetylase complexes using protein interaction modulators

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Project Summary Strategies to identify novel therapeutics typically include targeting enzymatic activities involved in relevant biological pathways, with the assumption that this approach will most likely identify potent, safe, and bioavailable drugs. This concept is particularly relevant to the development of epigenetic perturbants such as histone deacetylase (HDAC) inhibitors, or “HDACis”. All seven FDA-approved HDACis bind in similar ways to promiscuous deacetylase enzymatic pockets. While such “enzymatic inhibitor” compounds are used successfully to treat T cell lymphomas and multiple myelomas, they remain limited in addressing other types of cancers. One of the major limitations of currently available HDACis is that, by systematically targeting HDAC enzymatic pockets, they show little specificity for various HDAC complexes responsible for the regulation of different subsets of genes, and consequently, they affect the transcriptional regulation of a large portion of the transcriptome. Our goal here is to develop an alternative model according to which “protein interaction modulators” perturb specific protein interactions in subsets of HDAC subcomplexes and thus have much narrower effects on the transcriptome of treated cells than conventional HDACis. The central hypothesis of this model is that perturbing specific HDAC subcomplexes rather than all HDAC complexes in a cell might result in much narrower transcriptional effects and yet confer potent anti-tumorigenic effects (Fig. 1). To test this hypothesis, we propose the three following specific aims. Aim 1. To determine the extent to which small-molecule perturbations of non-enzymatic subunits of HDAC complexes can affect their repressing functions. Our goal is to identify a new class of HDAC modulators, which, instead of targeting enzymatic pockets, would affect other, more specific functions of HDAC complexes. Aim 2. To compare global transcriptomic effects of HDAC non-enzymatic versus enzymatic small- molecule perturbations. One branch of our central hypothesis is that it should be possible to identify HDAC complex modulators that result in much narrower transcriptional effects than those observed with conventional HDAC enzymatic inhibitors. Here we will determine transcriptome-wide effects of HDAC subcomplex modulators to investigate how widely or narrowly these new compounds affect the transcriptome. Aim 3. To test the hypothesis that promoter occupancy perturbations of HDAC complexes can potently abrogate tumorigenic phenotypes. We will test to what extent perturbing specific HDAC subcomplexes rather than all cellular HDAC complexes, while resulting in much narrower transcriptional effects, might nevertheless confer potent anti-tumorigenic effects. In short, we propose that instead of affecting all HDAC activities in the cell as conventional HDAC inhibitors do, a new class of protein interaction modulators can be identified that affect specific HDAC subcomplexes.