Synthesis and pharmacological characterization of novel histone deacetylase 6 inhibitors

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Histone deacetylases (HDACs) are epigenetic regulators catalyzing the deacetylation of lysine residues in proteins. HDACs are often overexpressed in cancer cells, in which they causally contribute to tumorigenesis. Histone deacetylase inhibitors (HDACi) inhibit protein deacetylation and alter gene expression and signaling. Consequently, cancer cell growth becomes compromised. HDACi are particularly effective against leukemia which is often not curable. Broad-range HDACi (pan-HDACi) inhibit several HDAC isoenzymes and produce general cytotoxicity. Isoenzyme-specific HDACi generate fewer side effects. Within the proposed project we plan to synthesize HDAC6 inhibitors with advanced chemistry (Prof. Mahboobi) and to test them in vitro and in cell based biological assays (PD. Dr. Krämer).HDAC6 has two catalytic domains and several specific functions and substrates. It is yet often unclear whether the catalytic activity of HDAC6 against certain substrates depends on both HDAC domains. The cytoskeletal protein tubulin-alpha and the chaperone HSP90 are targets of HDAC6. Deacetylated HSP90 assists the folding of oncoproteins including the leukemia fusion proteins BCR-ABL, AML1-ETO, and PML-RARalpha, mutant FLT3-ITD, the pan-leukemic marker protein WT1, and oncogenic p53. These and further cancer-relevant substrates of HDAC6 suggest the usefulness of HDAC6 inhibitors. The biological role of HDAC6 is though still incompletely understood and there are some controversies. These partly originate from the use of compounds that were erroneously assumed to be specific for HDAC6. In preliminary studies, we have synthesized novel and potent HDAC6 inhibitors. They exhibit potent cytotoxic and cytostatic activity in several cancer cell lines. We also show for the first time that the expression of survivin, a promoter of tumorigenesis and chemoresistance, depends on HDAC6. Moreover, our new inhibitors demonstrate combined cytotoxic activity with Imatinib against BCR-ABL transformed leukemic cells. At the molecular level this effect is linked to the depletion of BCR-ABL and WT1 and an accumulation of acetylated tubulin-alpha.Based on these data as well as on docking studies with crystal structures and homology models, we will synthesize and characterize even more potent and specific HDAC6 inhibitors. Furthermore, we aim to develop irreversible inhibitors for HDAC6. Such agents are a new pharmacological principle of HDAC6 inhibition. We expect that lower drug doses will sufficiently block HDAC6 due to a lesser detachment from HDAC6. The initial biological characterization of our new compounds targeting HDAC6 will mainly investigate their potential as pharmacological agents for the treatment of acute and myeloid leukemia. Data that we will collect with our novel inhibitors can also generally increase our understanding of the molecular effects and biological functions of HDAC6 in tumor cells.