Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression.
[8] Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription.
A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models.
Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents.
As of 2005, some examples in decreasing order of the typical zinc binding affinity were:[12] As of 2007, "second-generation" HDIs included the hydroxamic acids : trichostatin A, vorinostat (SAHA), belinostat (PXD101), resminostat, abexinostat, givinostat, LAQ824, ivaltinostat, nanatinostat and panobinostat (LBH589); and the benzamides : entinostat (MS-275), tacedinaline (CI994), zabadinostat, and mocetinostat (MGCD0103).
HDIs can alter the degree of acetylation nonhistone effector molecules and, therefore, increase or repress the transcription of genes by this mechanism.
Examples include: ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, MKP-1, NF-κB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc.
In animal models, these types of trauma have been shown to have significant effects on histone acetylation, particularly at gene loci which have known connection to behavior and mood regulation.
[24] Because of the massive effect of pan-HDAC inhibition, witnessed by the very low dosage concentration used and by the countless biological functions affected, many scientists have focused their attention on combining the less specific HDACi treatment with other more specific anti-cancer drugs, such as the efficacy of the combination treatment with the pan-HDAC inhibitor LBH589 (panobinostat) and the BET bromodomain JQ1 compound.
[26] One study noted the use of panobinostat, entinostat, romidepsin, and vorinostat specifically for the purpose of reactivating latent HIV in order to diminish the reservoirs.
[27] Another study found that romidepsin led to a higher and more sustained level of cell-associated HIV RNA reactivation than vorinostat in latently infected T-cells in vitro and ex vivo.