Isoform-Selective HDAC Inhibition in Autoimmune DiseaseNicole L Regna1* and Christopher M Reilly2

Abstract

Histone deacetylases are a class of enzymes that play an important role in protein modification and cellular function. Ongoing research suggests that HDAC inhibitors may be efficacious in the treatment of a wide range of diseases from cancer to autoimmune disease. HDACi therapy has shown promising results both in vitro and in vivo for the treatment of autoimmune disease. To date, 18 isoforms of HDACs have been identified, which exist in four different classes: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10) class III (sirtuins1-7), and class IV (HDAC11). The mechanism of action through which HDACs function remains to be fully elucidated. However, the use of isoform-selective HDAC inhibitors has been helpful in determining the physiological role of individual HDACs as well as in decreasing the toxicity of HDACi therapy. This review will focus on isoform-selective HDACs and how they may be effective for the treatment of autoimmune disease.

Unusually Large Young’s Moduli of Amino Acid Molecular Crystals

“…[10][11][12][13] Partly,this interest is driven by practical issues,asmechanical considerations affect the stability of molecular solids across ad iverse range of applications,from pharmaceuticals [3,[14][15][16] to energetic materials. [4,5] But the research is also driven by basic science,assome molecular solids exhibit Youngs moduli much higher than that expected from naive considerations.…”

“…[43] Thec omputed Youngs moduli obtained along the experimentally accessible crystallographic directions,aswell as the minimum and maximum values,are given in Table 1. Three-dimensional renderings of the anisotropy of Youngs moduli [41,14] are given in Figure 2.…”

Enantioselective synthesis and biological investigation of tetrahydro‐β‐carboline‐based HDAC6 inhibitors with improved solubility

“…HATs attach acetyl groups to lysine residues in histone and nonhistone proteins which provoke transcriptional activities, while HDACs catalyze the removal of acetyl groups causing chromatin to become highly packaged and, therefore, resulting in repressed gene expression . Overexpression of these enzymes correlate with several diseases including cancer, inflammation, neurodegenerative, and metabolic disorders . Therefore, histone deacetylase inhibitors represent an effective way to prevent the dysregulation of HDACs …”

Combined comparative molecular field analysis, comparative molecular similarity indices analysis, molecular docking and molecular dynamics studies of histone deacetylase 6 inhibitors

“…Histone deacetylation assists the condensation of chromatin which further promotes transcriptional repression. HDAC inhibitors (HDACIs) have been identified as anticancer agents (Drummond et al, 2005;Guha, 2015;Mottamal, Zheng, Huang, & Wang, 2015;Qiao et al, 2013), immune modulators (Adcock, Ito, & Barnes, 2005;Choi & Reddy, 2011;Dinarello, Fossati, & Mascagni, 2011;Faraco, Cavone, & Chiarugi, 2011;Halili, Andrews, Sweet, & Fairlie, 2009;Huber et al, 2007;Kawabata et al, 2010;Leoni et al, 2005;Perl, 2010;Reddy et al, 2008;Regna & Reilly, 2014;Reilly, Regna, & Mishra, 2011;Villeneuve & Natarajan, 2010;Woan, Sahakian, Sotomayor, Seto, & Villagra, 2012) and are useful in neurodegenerative disorders (Abel & Zukin, 2008;Kazantsev & Thompson, 2008). Till date, 18 individual HDACs have been identified, which are classified into four major classes based on their sequence similarity to yeast counterpart (Dokmanovic, Clarke, & Marks, 2007).…”