Histone Deacetylase Inhibitors: From Bench to Clinic

Paris, Marielle; Porcelloni, Marina; Binaschi, Monica; Fattori, Daniela

doi:10.1021/jm7011408

Cited by 358 publications

(257 citation statements)

References 119 publications

Supporting

Mentioning

254

Contrasting

Unclassified

Order By: Relevance

“…n spite of the significant progress made in HDAC research, [1][2][3][4] the quest for isoform-selective inhibitors continues to present a major challenge. [5][6][7] To date, detailed biostructural information is available only regarding a few among the known 11 metallo-enzymes.…”

mentioning

confidence: 99%

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

Hanessian

Auzzas

Larsson

et al. 2010

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

The inhibitory activity of an ω-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorption and metabolism studies were performed, which positioned this compound as a potential candidate for further preclinical studies and delineated measures for improving its pharmacokinetic profile.KEYWORDS HDAC promiscuous inhibitors, SAHA analogues, HDAC1-11 profile, class IIa-specific profile, absorption and metabolism I n spite of the significant progress made in HDAC research, 1-4 the quest for isoform-selective inhibitors continues to present a major challenge. [5][6][7] To date, detailed biostructural information is available only regarding a few among the known 11 metallo-enzymes. 1,[8][9][10][11] Consequently, the design of isoform-and class-selective inhibitors is somewhat arbitrary and derivative. 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. 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 judicious inclusion of specific appendages capable of interacting with specific residues in the cap region of HDACs can provide valuable structural, functional, and stereochemical insight into the design of new inhibitors.In a previous study, we determined the optimal alkyl chain length for activity against a single isoform, HDAC2. 20 Designed for understanding the role of the chirality in simple ω-alkoxy analogues of Vorinostat, compound (R/S)-2 emerged as a promising lead for its preliminary cytotoxic activity against leukemia, colon, and lung tumor cell lines. Here, we describe the details for the improved and shortened synthesis of 2, together with the biostructural insights through molecular modeling and a preliminary study of its in vitro activity against an extended panel of HDACs.Although relatively simple in conception, the previous nine-step synthesis of racemic 2 20 was shortened and adapted to produce gram-scale material for pharmacological studies (Supporting Information) (Scheme 1). The required 8-carbon chain of (R/S)-2 was assembled by a cross metathesis reac...

show abstract

mentioning

confidence: 99%

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

Hanessian

Auzzas

Larsson

et al. 2010

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…HDAC inhibitors have attracted considerable interest as drug targets in recent years, with several compounds of this class currently in clinical testing (30,31). Despite the broad applications of HDAC inhibitors in cell culture, animal models, and early phase clinical trials, surprisingly little is known about the expression of their targets in cancer tissues (32).…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4

Kim

2009

Int J Oncol

View full text Add to dashboard Cite

Abstract. Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents that act by inhibiting cancer cell proliferation and inducing apoptosis both in vitro and in vivo. This study examined the anti-tumor effect of apicidin on human endometrial cancer Ishikawa cells in an animal model by inhibiting specific HDAC expression. Nude mice were injected subcutaneously (s.c.) with Ishikawa cells, and the levels of cell proliferation and apoptosis were measured in the tumor tissues after an apicidin treatment. The expression patterns of a specific HDAC class by apicidin were measured in Ishikawa endometrial cancer both in vitro and in vivo. The tumor volume and weight were measured after the apicidin treatment. Apicidin significantly increased the acetylated histone H3 levels in an Ishikawa cells in vitro culture but the levels of HDAC3 and HDAC4 expression were significantly decreased. Apicidin suppressed the tumor growth of transplanted Ishikawa cells, the expression of proliferative cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) in tumor xenograft model, respectively. The inhibitory effect of apicidin on tumor growth was mediated in part through the down-regulation of HDAC3 and HDAC4. We suggest that apicidin is an effective anti-tumor agent on human endometrial cancer cells, and acts by regulating cell proliferation and apoptosis through the down-regulation of HDAC3 and HDAC4.

show abstract

“…[5][6][7] Breast cancer is one of the most common malignant tumors in women, despite major recent advances in therapy, more effective approaches to the treatment and prevention are necessary. HDACis such as Vorinostat (Zolinza ® , SAHA) approved by FDA for treatment of cutaneous T-cell lymphoma (CTCL) a novel series of N-hydroxy-4-(3-phenylpropanamido)benzamide (hppB) derivatives comprising N-hydroxybenzamide group as zinc-chelating moiety were designed, synthesized and evaluated as histone deacetylases inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer

Feng

Fang²,

Wang³

et al. 2011

Cancer Biology & Therapy

View full text Add to dashboard Cite

Histone Deacetylase Inhibitors: From Bench to Clinic

Cited by 358 publications

References 119 publications

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

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

Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4

Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer

Contact Info

Product

Resources

About