Strategies in developing promising histone deacetylase inhibitors

Abstract

Histone deacetylases (HDACs) are a family of enzymes that have been of interest in drug discovery for more than 30 years. Inhibitors of HDACs are potential therapeutics for various diseases, such as neurodegenerative diseases, inflammation, viral infection, and especially cancer. Most HDAC inhibitors (HDACi) are designed for cancer therapy. In 2006, suberoylanilide hydroxamic acid was approved by the US Food and Drug Administration for once-daily oral treatment of advanced cutaneous T-cell lymphoma. In the meantime, there have been aggressive efforts to bring HDACi to the market for every major tumor type, either as a single therapy or in combination, and a number of compounds are currently undergoing clinical trials. Multiple strategies have been applied to the rational design of drugs targeting HDACs by taking advantage of the new developments in proteomics, chemogenomics, cheminformatics, and computational chemistry/biology. Herein, we review the current methods successfully used in developing novel HDACi.

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

“…[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.…”

“…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.…”

“…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.…”

Synthesis and Antiproliferatory Activity of Novel Diphyllin Hydroxamic Acid and Mercaptan Derivatives

“…组蛋白去乙酰化酶抑制剂(HDACI) 可以使染色质组蛋白乙酰化水平提高, 导致特定基因表 达激活, 相应地导致细胞的末端分化或癌细胞的凋亡, 因此组蛋白去乙酰化酶(HDAC)已成为抗肿瘤药物研发 领域重要的靶标 [1,2] . 目前上市 HDACI SAHA (N-羟基-N'-苯基辛二酰胺)为广谱 HDACI, 具有明显的胃、 血液、 心脏以及神经毒性.…”