Suberoylanilide hydroxamic acid

Kelly WK, Marks PA (2005) Drug insight histone deacetylase inhibitors - development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2 150-157... 

One of the first HDAC inhibitors to be identified and characterized was sodium butyrate, where it was found to alter the histone acetylation state (Riggs et al, 1977), and further determined to inhibit HDAC activity both in vitro and in vivo (Candido et al, 1978). Almost a decade later trichostatin A (TSA), a fungistatic antibiotic, was found to induce murine erythroleukemia cell differentiation (Yoshida et al, 1987). To date, a wide range of molecules have been described that inhibit the activity of Class I and Class II HDAC enzymes, and with a few exceptions, can be divided into structural classes including (1) small-molecule hydroxamates, such as TSA, suberoylanilide hydroxamic acid (SAHA), scriptaid and oxamflatin (2) short-chain fatty-acids, such as sodium butyrate, sodium phenylbutyrate and valproic acid (VPA) (3) cyclic tetrapeptides, such as apicidin, trapoxin and the depsipeptide FK-228 and (4) benzamides, such as MS-275 and Cl-994 (for reviews see Remiszewski et al, 2002 Miller et al, 2003). Some of these molecules are represented in Fig. 4. 

Suberoylanilide hydroxamic acid (SAHA) Class I/II Richon et al., 1998... 

Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM (2000) Suberoylanilide hydroxamic acid An inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60 5165-5170... 

HDAC inhibitors have received tremendous attention with the recent FDA approval of Vorinostat (Zolinza) or suberoylanilide hydroxamic acid (SAHA) for the treatment of cutaneous T-cell lymphoma (CTCL). Multiple compounds have thus entered into clinical trials for a wide variety of diseases. Many of these compounds were inspired in some part from HDAC natural product inhibitors. In addition, one natural product Romidepsin has also gained FDA approval for treating cutaneous T-cell lymphoma. 

Duvic, M. and Zhang, C. (2006) Clinical and laboratory e5q>erience of vorinostat (suberoylanilide hydroxamic acid) in die treatment of cutaneous T-cell lymphoma. British Journal of Cancer, 95, S13—S19. 

One interesting pharmacokinetic phenomenon observed with tasidotin was that parent concentrations prior to ending the infusion were higher than at the end of the infusion (Fig. 13.9). For a drug with constant clearance, this should not be possible. Although unusual, this phenomenon is not unheard of, having been reported for suberoylanilide hydroxamic acid, a histone deacetylase inhibitor [26]. In that report, the authors could not postulate a reason for such pharmacokinetic behavior. The same effect has also been reported for furosemide, perhaps due to the drug s behavior within the renal tubule [27]. 

Hydroxyamic acids Suberoylanilide hydroxamic acid (SAHA) Apoptosis, differentiation, and cell cycle arrest... 

SAHA Vorinostat, suberoylanilide hydroxamic acid, brand name Zolinza, a class of agents known as histone... 

E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihyxlroquinazolin-6-yl)-N-hydroxyacrylamide N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydro-quinazolin-7-yl)- acrylamide Suberoylanilide hydroxamic acid Valproic acid... 

Histone deacetylase (HDAC) inhibitors ameliorate a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the FDA for the sole use of cancer therapy. SAHA also showed neurotrophic and neuroprotective effects in... 

Chen SH, Wu HM, Ossola B, Schendzielorz N, Wilson BC, Chu CH et al (2011) Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage. Br J Pharmacol 165 494-505... 

Hockly E et al (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington s disease. Proc Natl Acad Sci USA 100(4) 2041-2046... 

Faraco G et al (2006) Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol 70(6) 1876-1884... 

Trichostatin A (35) is structurally related to suberoylanilide hydroxamic acid (SAHA), a molecule that has reached the market as a therapy for the treatment of cutaneous T-cell lymphoma (CTCL), marketed as vorinostat. ° Hybrid derivatives have been synthesized combining features of trichostatin A and fungal-derived cyclic tetrapeptides such as trapoxin and apicidin, which show subnanomolar activities/ ... 

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