HDAC inhibitors HDACi

Histone deacetylases are linked to the pathogenesis of malignancy from a mechanistic perspective. The capacity of HDAC inhibitors (HDACi) to interfere with the enzyme fimction has led to the observed prechnical and clinical activity in cancer therapy. Although the exact mechanism of anti-tumor activity is not fully elucidated, various cellular pathways have been shown to be involved. From the first chnical trials involving HDACi with short chain fatty acids to the newer generation hydroxamic acid derivatives and cychc tetrapeptides, a number of structurally diverse compounds have made the transition from the laboratory to the chnical arena. For purposes of this part of the discussion, HDACi are arbitrarily divided into the hydroxamates and nonhydroxamates. 

HDACs represent a rational monotherapy or combination therapy for cancer treatment. Several HDAC inhibitors (HDACi s) are currently under clinical trials either as monotherapy or combination therapy agents against cancer [43]. The hydroxamate-containing HDACi s trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA, 13) exhibit the highest potency with excellent efficacy. 

The histone deacetylases (HDACs) are able to regulate gene expression, and HDAC inhibitors (HDACIs) hold considerable promise in the treatment of cancer and a variety of neurodegenerative diseases. Modifications to the zinc binding group (ZBG) of the HDACIs can influence HDAC inhibitory potency, isoform selectivity, and neurotoxicity. We provide data that compare the ability of three... 

Crystal structures of a histone deacetylase-like protein (HDLP) and HDAC8 have confirmed a general pharmacophore model for HDAC inhibitors, comprising a cap joined by a hydrophobic linker to a zinc-binding group (ZBG). This model is exemplified by SAHA and the natural product HDACi Trichostatin A (TSA) 2. 

All four members of this class of HDAC have been demonstrated to be sensitive to HDAC-specific inhibitors (HDACi) such as trichostatin A (TSA). It is noteworthy that the HDACi Valproic acid (VPA), in addition to selectively inhibiting the catalytic activity of class I HDACs, induces proteasomal degradation of HDAC2, in contrast to other inhibitors such as TSA (Kramer et al, 2003). 

Figure 4. Therapeutic strategies to counteract CBP loss of function. CBP loss of function leads to a decrease in histone acetylation levels as well as a decrease in CBP-dependent transcription. Two main approaches can be tested to reverse diis process either resetting HAT functionality or resetting global acetylation levels widi die use of HDAC inhibitors. Whereas both strategies would increase histone acetylation levels, HDAC inhibition would act on a broad range of genes, while CBP activation (overexpression or by a pharmacological approach) would specifically target bodi CBP-dependent histone acetylation and transcription. The structure of some of the HDACi that have been tested in different models, such as small fatty acids and hydroxamic acids, are represented in the boxes...

Of note, a very recent report shows that SIRTl (sirtuin class of HDAC), that was shown to participate in axonal protection (Araki et al, 2004), could be acting in a neuroprotective way in ALS (Fischer et al, 2005). As noted earlier, this class of HDAC is insensitive to classical HDAC inhibitors, but it should be kept in mind reinstating acetylation homeostasis with classical HDACi might indirectly biased sirtuin s regulations as well. 

Figure 9.2 Representative HDACis and proposed HDAC inhibitor pharmacophore.

The HDACi s mentioned above inhibit exclusively Zn2+-dependent HDACs and not the NAD-dependent Sittuins. Researcher also focuses on development of sirtunin inhibitors and first successes like the compound siitinol have been repotted. Finally, the development of HAT inhibitors is also pursued and to date some compounds like the peptide-based inhibitor H3-CoA-20 or the small molecule MB-3 are among the first molecules to show HAT inhibition [3]. 

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