proteases. Nucleophilic attack of water onto the carbonyl leads to the formation of a tetrahedral intermediate, stabilized by two zinc-oxygen interactions, similar to zinc proteases, and possibly by a hydrogen bond with the Tyr-303 hydroxyl (10.25). In the final step, the tetrahedral intermediate evolves by cleavage of the C-N bond with concomitant protonation from another histidine-aspartic charge-relay system (10.26).

HDAC inhibitors can be classified into four main categories, namely, short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides, and benzamides.

3.2.1. Short-chain fatty acids

They normally have low potencies, but have become a useful tool in the study of HDAC inhibitors. Butyric and valproic acids were the first known HDAC inhibitors. Tributyrin is a prodrug of butyric acid with favorable pharmacokinetic and efficacy profiles, which has entered clinical studies for solid tumors.75 Valproic acid, an anticonvulsant drug, is a dual inhibitor of HDAC1 and HDAC2 and is used for the treatment of acute myelogenous leukemia in elderly patients, in combination with all-trans retinoic acid.76

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