Histone Deacetylase Inhibitors

Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones, which include the dynamic acetylation and deacetylation of epsilon-amino groups of lysine residues present in the tail of core histones.¹

The enzymes responsible for reversible acetylation/-deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively.²

HATs act as transcriptional coactivators, and HDACs are part of transcriptional corepressor complexes.³

Mammalian HDACs can be divided into three classes according to sequence homology.⁴

• Class I consists of the yeast Rpd3-like proteins (HDAC1, HDAC2, HDAC3, and HDAC8).
• Class II consists of the yeast Hda1-like proteins (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10).⁵ Class II HDACs have been implicated in the regulation of muscle differentiation.⁶ Interaction of HDAC4, -5, and –7 with members of the MEF2 family of transcription factors represses their transcriptional activity and prevents myogenesis.⁷ The deacetylase activity of class II HDACs is regulated by subcellular localization.⁴
• Class III comprises the yeast Sir2-like proteins. Class I HDACs are ubiquitously expressed, and most class II HDACs are tissue-specific.²

Inhibitors of histone deacetylase inhibitors induce hyperacetylation of histones that modulate chromatin structure and gene expression. These inhibitors also induce growth arrest, cell differentiation, and apoptosis of tumor cells.⁸

A2478 APHA Compound 8

• 3-(1-Methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide
• C₁₆H₁₆N₂O₃
• MW 284.3
• A new synthetic histone deacetylase inhibitor inducing histone hyperacetylation, growth inhibition, and terminal cell differentiation.⁹

A8851 Apicidin

• Cyclo[(2S)-2-amino-8-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]
• C₃₄H₄₉N₅O₆
• MW 623.8B
• CAS# 183506-66-3
• Subject of US Patent No. 5,620,953. Manufactured and sold under license from Merck& Co., Inc. Potent (nM) cell permeable inhibitor of histone deacetylase. Also, exhibits antiprotozoal and potential antimalarial properties. Apicidin has antiproliferative activity on HeLa cells accompanied by cell arrest at the G1 phase. In addition, it induces selective changes in the expression of p21 and gelsolin.^{10,11,12,12,14}

B5887 Sodium Butyrate

• Butyric Acid Sodium salt
• C₄H₇NaO₂
• MW 110.1
• CAS# 156-54-7
• Decreases Ca²⁺ release from intracellular stores. Inhibits histone deacetylase (HDAC).¹⁵ Induces apoptosis in several cell lines.

D5816 (-)-Depudecin

• 4,5:8,9-Dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienitol
• C₁₁H₁₆O₄
• MW 212.2
• CAS # 139508-73-9
• Inhibitor of histone deacetylase (HDAC) both in vivo and in vitro. Alters the spindle shaped morphologhy of v-Ha-ras-transformed NIH3T3 cells to a flattened shape and induces an intricate actin stress fiber network in these cells and in MG63 osteosarcoma cells. Also exhibiits anti-angiogenic activity.^16,17,18

S7817 Scriptaid

• 6-(1,3-Dioxo-1H, 3H-benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxyamide
• C₁₈H₁₈N₂O₄
• MW 326.3
• CAS # 287383-59-9
• Histone deacetylase inhibitor with lower toxicity than trichostatin A, used to enhance protein expression.⁹

S7942 Sirtinol

• 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide
• C₂₆H₂₂N₂O₂
• MW 394.5
• Inhibits yeast Sir2p transcriptional silencing activity in vivo, yeast Sir2p and human SIRT2 deacetylase activity in vitro.

T8552 Trichostatin A

• [R-(E,E)]-7-[4-(Dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide
• C₁₇H₂₂N₂O₃
• MW 302.4
• CAS# 58880-19-6
• Inhibits histone deacetylase at nanomolar concentrations; resultant histone hyperacetylation leads to chromatin relaxation and modulation of gene expression. May be involved in cell cycle progression of several cell types, inducing cell growth arrest at both G and G/M phases; may induce apoptosis. Enhances the efficacy of anticancer agents that target DNA. Found to modulate CD4+ T-cell responses.20,21, 22

References:

1. Wang, A.H., et al., Mol. Cell. Biol., 19, 7816-7827 (1999)
2. Grozinger, C.M., et al., Proc. Natl. Acad. Sci. USA, 96, 4868-4873 (1999)
3. Fischle, W., et al., Biochem. Cell Biol. , 79, 337-348 (2001)
4. Khochbin, S., et al., Curr. Opin. Genet. Dev. , 11, 162-166 (2001)
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8. Moreira, J.M.A., BMC Cancer , 3, 30 (2003)
9. Su, G., et. al., Cancer Res. , 60, 3137-3142 (2000)
10. Mai, A., et. al., J. Med. Chem., 45, 1778-1784 (2002)
11. Kwon, S.H., et al., J. Biol. Chem. , 18, 2073 (2002)
12. Colletti, S.L., et al., Bioorg. Med. Chem., 11, 107 (2001)
13. Kim, J.S., et al., Biochem. Biophys. Res. Comm. , 281, 866 (2001)
14. Han, J.W., et al., Cancer Res. , 60, 6068 (2000)
15. Cuisset, L., et, al., Biochem. Biophys. Res. Comm. , 246, 760-764 (1998)
16. Kwon, et al., Proc. Natl. Acad. Sci. USA, 95, 3356 (1998)
17. Martin, et al., Proc. Natl. Acad. Sci. USA, 95, 3335 (1998)
18. Shimada, et al., Chemistry and Biology, 2, 517 (1995)
19. Grozinger, C.M., et. al., J. Biol. Chem. , 276, 38837 (2001)
20. Yoshida, M., et al., Bioessays, 17, 423-430 (1995)
21. Kim, M.S., et al., Cancer Res. , 63, 7291-7300 (2003)
22. Moreira, J.M.A., et. al., BMC Cancer, 3, 30 (2003)

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