Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical trials as anti-cancer drugs. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. This tutorial review focuses on the recent progress toward the identification of class-selective and isoform-selective HDAC inhibitors. The emerging trends suggest that subtle differences in the active sites of the HDAC isoforms can be exploited to dictate selectivity.

Inhibitors of histone deacetylase (HDAC) proteins such as suberoylanilide hydroxamic acid (SAHA) have emerged as effective therapeutic anti-cancer agents. To better understand the structural requirements of HDAC inhibitors, a small molecule library with a variety of substituents attached adjacent to the metal binding hydroxamic acid of SAHA was synthesized. The presence of a substituent adjacent to the hydroxamic acid led to an 800 to 5000-fold decrease in inhibition compared to SAHA. The observed results have implications for drug design, suggesting that HDAC inhibitors with substituents near the metal binding moiety will have inhibitory activities in the μM rather than nM range.Suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza ™ ) recently gained FDA approval for the treatment of advanced cutaneous T-cell lymphoma (CTCL). 1 SAHA is an inhibitor of histone deacetylase (HDAC) proteins, which are linked to a variety of cancers. 2 While SAHA is the first HDAC inhibitor (HDACi) to meet FDA approval, several other small molecules that inhibit HDAC proteins are currently in clinical trials for cancer treatment. 3 Distinguishing characteristics of HDAC inhibitors include a metal binding moiety, a carbon linker, and a capping group (Figure 1). Based on crystallographic analyses, the capping group is solvent-exposed and interacts with amino acids near the entrance of the active site, while the metal binding moiety resides in the protein interior and complexes the metal ion involved in catalysis. 4-6 The linker serves to position the capping and metal binding groups appropriately for high affinity interactions with proteins. With a modular framework and application towards cancer treatment, HDAC inhibitors are viable targets for future drug design.Previous HDACi design has emphasized modification of the capping group and the metal binding moiety. In the case of the metal binding moiety, SAHA contains a hydroxamic acid while other inhibitors contain thiols, epoxides, carboxylates, or benzamides. 7,8 For example, two HDAC inhibitors in clinical trials, MS-275 and valproic acid (Figure 1), contain benzamide and carboxylate metal binding moieties, respectively, 9,10 and display IC 50 values of 2 μM and 400 μM. 11,12 The reduced inhibitory activities compared to SAHA (110-370 nM IC 50 ) 13, 14 are partially explained by the presence of the benzamide or carboxylic acid group. 7,15,16Interestingly, MS-275 displays modest preference toward select proteins within the eleven member HDAC family. 17 Selective HDAC inhibitors would aid in elucidating the role of each individual HDAC protein in cancer and have the potential to be better drugs. 18 However, strictly selective HDAC inhibitors have yet to be discovered.In addition to altering the metal binding moiety towards HDACi design, the hydrocarbon linker has been diversified, focusing on altering chain length, creating points of unsaturation along Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a servi...

Histone deacetylase (HDAC) proteins are epigenetic regulators that deacetylate protein substrates, leading to subsequent changes in cell function. HDAC proteins are implicated in cancers, and several HDAC inhibitors have been approved by the FDA as anticancer drugs, including SAHA (suberoylanilide hydroxamic acid; Vorinostat and Zolinza). Unfortunately, SAHA inhibits most HDAC isoforms, which limits its use as a pharmacological tool and may lead to side effects in the clinic. In this work SAHA analogues substituted at the C2 position were synthesized and screened for HDAC isoform selectivity and in cells. The most potent and selective compound, C2--hexyl SAHA, displayed submicromolar potency with 49- to 300-fold selectivity for HDAC6 and HDAC8 compared to HDAC1, -2, and -3. Docking studies provided a structural rationale for selectivity. Modification of the nonselective inhibitor SAHA generated HDAC6/HDAC8 dual selective inhibitors, which can be useful lead compounds toward developing pharmacological tools and more effective anticancer drugs.

Histone deacetylase (HDAC) proteins have emerged as targets for anti-cancer therapeutics, with several inhibitors used in the clinic, including suberoylanilide hydroxamic acid (SAHA, vorinostat). Because SAHA and many other inhibitors target all or most of the 11 human HDAC proteins, the creation of selective inhibitors has been studied intensely. Recently, inhibitors selective for HDAC1 and HDAC2 were reported where selectivity was attributed to interactions between substituents on the metal binding moiety of the inhibitor and residues in the 14-Å internal cavity of the HDAC enzyme structure. Based on this earlier work, we synthesized and tested SAHA analogs with substituents on the hydroxamic acid metal binding moiety. The N-substituted SAHA analogs displayed reduced potency and solubility, but greater selectivity, compared to SAHA. Docking studies suggested that the N-substituent accesses the 14-Å internal cavity to impart preferential inhibition of HDAC1. These studies with N-substituted SAHA analogs are consistent with the strategy exploiting the 14-Å internal cavity of HDAC proteins to create HDAC1/2 selective inhibitors.

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