The use of diversity profiling to characterize chemical modulators of the histone deacetylases

Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools

“…1,7,[12][13][14] In addition, complete data regarding the factual HDAC profile for most of the early discovered agents are not available, since the development of effective isozyme-based assays is relatively recent. [5][6][7][15][16][17][18] As a consequence of the complex, pleiotropic nature of cancer, promiscuous HDAC inhibitors such as Vorinostat (1) (SAHA, suberoylanilide hydroxamic acid) 19 ( Figure 1) seem superior and as safe in the clinic as compared to the few class-specific agents available. [5][6][7]15 Ligand-based approaches are a first-choice solution to delineate the structural requirements for HDAC selectivity, especially with the emergence of ω-aryl alkanoyl hydroxamates such as Vorinostat as clinical candidates.…”

“…[5][6][7][15][16][17][18] As a consequence of the complex, pleiotropic nature of cancer, promiscuous HDAC inhibitors such as Vorinostat (1) (SAHA, suberoylanilide hydroxamic acid) 19 ( Figure 1) seem superior and as safe in the clinic as compared to the few class-specific agents available. [5][6][7]15 Ligand-based approaches are a first-choice solution to delineate the structural requirements for HDAC selectivity, especially with the emergence of ω-aryl alkanoyl hydroxamates such as Vorinostat as clinical candidates. 1,7,[12][13][14] In this regard, simple and readily accessible surrogates are worthy of study, provided that they bear pharmacophoric determinants as close as possible to a maximum common substructural consensus required to target the whole HDAC panel.…”

“…The generality of this observation must be validated by a careful scrutiny of the appropriate substrates and the purity of recombinant isoenzymes enabling accurate HDAC profiling. 3,[5][6][7][15][16][17] Preliminary assays were performed on (R/S)-2 to assess its absorption and metabolism. Human colorectal carcinomaderived cells (Caco-2 cell line) were used as an established in vitro model for the prediction of (R/S)-2 absorption across the human intestine.…”

NF‐κB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress

“…RelA acetylation can be modified by using HDAC inhibitors that have already proved to be effective in attenuating neurological deficits and neuronal loss in various animal models of brain ischemia (Kim et al, 2007;Ren et al, 2004), Huntington's disease (Ferrante et al, 2003;Gardian et al, 2005;Hockly et al, 2003), spinal muscular atrophy (Chang et al, 2001), amyotrophic lateral sclerosis (Corcoran et al, 2004;Petri et al, 2006;Ryu et al, 2005), and experimental autoimmune encephalomyelitis . Among HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA) and MS-275 (entinostat) are effective in inhibiting the HDAC1, HDAC2 and HDAC3 isoforms (Blackwell et al, 2008) that are the most involved in RelA deacetylation (Ashburner et al, 2001;Chen and Greene, 2004;Zhong et al, 2002). On the other side, the specific deacetylation of RelA at the K310 residue could be achieved by using the SIRT1 activator resveratrol which reduces pro-apoptotic transcription and rescues neuronal cells from apoptosis (Lanzillotta et al, 2010).…”

Sodium Butyrate Inhibits the Self-Renewal Capacity of Endometrial Tumor Side-Population Cells by Inducing a DNA Damage Response

“…Histone deacetylases (HDAC) and histone acetyl transferases are enzymes that ensure the homeostatic levels of histone acetylation. Deregulated HDAC activity has been found in certain human cancers (18)(19)(20)(21)(22). Several studies have shown the antiproliferative or the proapoptotic effects of HDAC inhibitors (HDACi) on endometrial cancer cells (23)(24)(25).…”