Molecular Design, Synthesis, and Pharmacology of Novel and Selective Histone Deacetylae 10 (HDAC10) Inhibitors

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Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers that fall into 4 classes. Histone deacetylase inhibitors (HDACi) are developed to correct dysregulated biological processes due to aberrant HDAC activities. HDAC6 and HDAC10 belong to the class IIb subgroup of the HDAC family. The targets and biological functions of HDAC10 are still ill-defined and no specific HDAC10 inhibitors with biological activity are published. We have synthesized and characterized the first specific inhibitors of HDAC10 and we demonstrate that these induce apoptosis of acute B cell leukemia and lymphoma cells. We aim to rationally improve our lead compounds by a combination of structure-based design, synthesis, in vitro testing as well as cellular characterization including genetic knockout strategies. Promising candidates can be selected based on the in vitro profiling using recombinant HDACs. We will test such inhibitors against a larger panel of leukemic cells regarding apoptosis induction. To comprehensively reveal the protein targets of HDAC10, we will use our new HDAC10 inhibitors in global proteome and transcriptome analyses. This will include a comparative analysis of leukemic cells that respond or resist apoptosis induction upon HDAC10 inhibition and we want to carry out functionally tests for new HDAC10 targets. To discover further innovative inhibitors of HDAC10, we will synthesize and test proteolysis targeting chimeras (PROTACs) that inhibit the catalytic activity of HDAC10 and additionally degrade it. Our new HDAC10 inhibitors are tools to identify the downstream targets and functions of HDAC10. Moreover, such compounds could prospectively be used as new treatment options for leukemia.