Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups from lysine residues on histones, decreasing the transcription of specific genes. There are 11 HDAC isoforms that share a zinc active site. The most unique is HDAC6 as it is found in the cytoplasm. HDAC6 targets cytosolic proteins including α-tubulin and Hsp90. HDAC6 deacetylates α-tubulin, decreasing microtubule formation, and intercellular transport. HDAC6s control of α-tubulin acetylation gives it control over processes including cell mobility and immune synapse formation. Because of HDAC6s impact it has been identified as a target for the treatment of several conditions. These include cancers such as triple negative breast cancer, as well as neurological diseases including Fragile X syndrome, and neurodegenerative disorders. Other HDACs have been identified as targets for treatment of the same conditions, but what sets HDAC6 apart is the knockdown of the HDAC6 gene has no negative side effects. While the knockdown of HDACs 1-3 have fatal effects. HDAC6 is an ideal target for the treatment of many conditions, but there are no HDAC6 selective inhibitors. There are currently FDA approved HDACIs that are not selective inhibitors. They are approved as anticancer agents that promote cell-cycle arrest, and apoptosis. These HDACIs have not seen usage outside of oncology due to the wide-reaching effects that lead to inconsistent results. They also have been shown to cause side effects as severe as cardiotoxicity and neurotoxicity. Current HDAC inhibitors follow a three-part composition containing a zinc binding group (ZBG), a linker, and a cap group. The most common ZBG is hydroxamic acid which has off target effects including interactions with the cardiac potassium channel. Hydroxamic acid also has poor pharmacokinetics, it can be hydrolyzed then degraded through glucuronidation. The cap group drives isoform selectivity, by interacting with the enzyme surface, which varies between different isoforms. By designing a cap group for HDAC6 isoform selectivity can be Improved. The basis of this research is to design novel HDAC6 selective inhibitors. The first line of inquiry is in the use of non-hydroxamic acid zinc binding groups, this will be directed towards groups with strong chelation abilities such as the thione group. The second line of inquiry focuses on the incorporation on novel cap groups with the goal of improving the binding affinity as well as the HDAC6 isoform selectivity. .

Designing histone deacetylase 6 selective inhibitors

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