Histone deacetylases are enzymes that catalyze the cleavage of acetyl groups from lysine residues of many proteins in the body, including histone proteins. This cleavage is particularly significant in histone proteins because these proteins bind to DNA and provide structure for chromosomes. With acetyl groups present, the chromosomes are expanded, and the DNA is readily available for transcription. On the contrary, after histone deacetylase activity, the chromosomes condense tightly through electrostatic interactions, blocking the DNA contained within from transcription. Overexpression of HDAC proteins can thus prevent the transcription of proteins necessary for the prevention of various disease states, including cancer, autoimmune disorders, and inflammatory responses. Previous research has shown that HDAC8 expression in particular is linked with lung, colon, and cervical cancer, and that subsequent RNA interference knockdown of HDAC8 can slow growth of these cancer cell lines. In addition to cancer, HDAC8 expression is associated with promoting viral entry of Influenza A and other viruses that use endocytosis as a late cell-penetration method, but the details of HDAC8’s role are not known. Four HDAC inhibitors have received FDA approval for various cancers, but they exhibit many side effects, which is believed to be due to their pan-HDAC activities. Recently, it was reported that a strategy to acquire HDAC8 selectivity is to construct HDAC inhibitors with an L-shaped configuration. Accordingly, we have designed and synthesized a variety of novel inhibitors spanning several chemotypes, all of which exhibit “L-shapes” and carry the crucial hydroxamic acid functional group to target the active site zinc ion. In addition, towards acquiring further gains in affinity, we have targeted Asp100 and Lys20 located on the surface of the protein near the entrance to the active site. We will present our current status in the discovery of HDAC8-selective inhibitors.

Design, synthesis, and biological evaluation of novel histone deacetylase 8 (HDAC8) inhibitors

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