Development of a generalizable chemo-proteomics screening platform for small molecule degraders applied to HDACs

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Project Summary Targeted protein degradation with small molecule degraders is an emerging therapeutic modality for cancer treatment. Degraders have several advantages compared with traditional inhibitor drugs that make them attractive new therapeutic entities. First, degraders can work at much lower concentration than inhibitors, thus can be used at lower dosage and have lower drug toxicity. Second, degraders remove the target protein altogether rather than simply inhibiting the enzymatic activity of the protein, thus eliminating the non-enzymatic activities of target proteins. Such non-enzymatic activities are especially common for histone deacetylases (HDACs). Third, degraders can be used to target targets considered “undruggable” by conventional means, which represent 80% of the human proteome, as long as a protein binding ligand is available. However, the current strategies to develop degraders follow a rather empirical route with fortuitous outcomes. Here we propose to develop a new screening platform to discover and develop degrader molecules. The strategy involves structure guided degrader library design based on promiscuous inhibitors that target a protein family followed by chemo-proteomics screening to identify degradable protein family members and selective degraders against them. The large amount of data from proteomics screens enables us to understand the relationship between the chemical structures of degraders and potency of target protein degradation, which feeds back to the next round of iterative library design and screening. Such iterative rounds of optimization with proteomics evaluation have proven to be a more effective way to generate selective and potent degraders for developing therapeutic candidates and chemical probes for biological studies. We apply this strategy to an important family of enzymes, HDACs, for which specific inhibitors are rarely available. HDACs are therapeutic targets for many different kinds of cancer and human diseases. We propose to develop selective degraders for a number of HDAC members. Particularly, we hope to develop HDAC8 degraders as a new therapeutic candidate for Ewing sarcoma, an aggressive cancer in children and young adults that have an urgent need for new therapeutic options. Secondly, we hope to develop selective HDAC6 degraders to test the proposed role of HDAC6 in inflammasome activation. We believe this strategy is widely applicable to other protein families and would make a significant impact in the field of developing degrader therapeutics.