Histone Deacetylase Inhibitors

Several HDAC inhibitors have been developed and investigated in preclinical models of solid and hematological malignancies, and a few are in early phase clinical trials. The HDAC inhibitors are generally divided into four groups including hydroxamic acids, cyclic peptides, aliphatic acids, and benzamides (13). The most common HDAC inhibitors that are currently in clinical investigations are listed in Table 1. Several HDAC isoenzymes have been identified and are designated HDAC 1 through 11. The isoenzymes are classified to type I, which includes HDAC1, HDAC2, HDAC3, HDAC8, and HDAC11, and type II, which includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. HDAC inhibitors may target several HDAC isoenzymes. Several HDAC inhibitors have been

TABLE 1 Histone Deacetylase Inhibitors in Clinical Investigation

Class

Compound

Hydroxamate

TSA

SAHA

CBHA

LBH-589

PXD-101

Cyclic peptide

Depsipeptide (FK-228)

Aliphatic acid

Valproic acid

Phenylbutyrate

Benzamide

MS-275

p-N-Acetyl dinaline (CI-994)

MGC0103

Abbreviations: CBHA, M-carboxycinnamic acid bis-hydroxamide; SAHA, sub-eroylanilide hydroxamic acid; TSA, trichostatin A.

Abbreviations: CBHA, M-carboxycinnamic acid bis-hydroxamide; SAHA, sub-eroylanilide hydroxamic acid; TSA, trichostatin A.

studied in phase I trials in hematological and nonhematological malignancies. Sub-eroylanilide hydroxamic acid (SAHA), depsipeptide, phenyl butyrate, MS-275, and LBH589 are currently in or nearing phase II investigations or in phase I studies testing combinations with other agents. Other agents, such as PXD-101 and MGO0103, are in early phase development. SAHA is currently under evaluation in several trials targeting breast cancer patients.

The HDAC inhibitors have demonstrated multiple effects in cancer cell lines. These effects include alteration of gene expression and differentiation, induction of cell death, reduced proliferation, and/or cell cycle arrest and are summarized in Table 2.

TABLE 2 Multiple Biologic Effects of Deacetylase Inhibition

Pathway

Effect

Induction of apoptosis

p53

DR4

Bax, Bak

#

FLIP

#

IAPs

#

Bcl-2, Bcl-xL

Induction of cell-cycle arrest

p21

p27

#

Cyclin D

#

CDK4

#

Thymidylate synthetase

Oncogene destabilization

#

BCR/abl

#

HER2/neu

#

EGFR

#

FLT-3

#

pAKT

#

ER-alpha

Antiangiogenesis

#

VEGF

#

Ang2

#

Tie2

#

HIF1-alpha

Abbreviations: FLIP, FLICE-inhibitory protein; IAP, inhibitor of apoptosis protein; HER2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; FLT, Fms-like tyrosine kinase; VEGF, vascular endo-thelial growth factor.

Abbreviations: FLIP, FLICE-inhibitory protein; IAP, inhibitor of apoptosis protein; HER2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; FLT, Fms-like tyrosine kinase; VEGF, vascular endo-thelial growth factor.

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