New and emerging HDAC inhibitors for cancer treatment
Alison C. West, Ricky W. Johnstone
Alison C. West, Ricky W. Johnstone
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(1):30-39. https://doi.org/10.1172/JCI69738.
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New and emerging HDAC inhibitors for cancer treatment

Abstract

Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.

Authors

Alison C. West, Ricky W. Johnstone

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Figure 2

The specificity of HDACis for HDACs and associated protein complexes.

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The specificity of HDACis for HDACs and associated protein complexes. Th...
The specificity of HDACis for HDAC isoforms has been recently reclassified using sophisticated chemoproteomics and chemical phylogenetic approaches, revealing that HDACis have surprising affinity for both HDACs and individual HDAC-dependent multiprotein complexes (34, 35). This new specificity is shown for class I HDAC1, -2, -3, and -8 as well as class IIb HDAC6 and -10; specificity is calculated from average KDapp values generated by Bantscheff et al. and Bradner et al. (34, 35). Illustration based on data from Deubzer et al. (94), Bolden et al. (40), Bantscheff et al. (34), and Bradner et al. (35). BHC80, BRAF35-HDAC complex protein; CHD4, chromodomain helicase DNA binding protein 4; CoREST, REST corepressor 1; LSD1, lysine-specific demethylase 1; MTA, metastasis-associated protein; MBD, methyl-CpG binding domain protein; NuRD, nucleosome remodeling and deacetylase; RbAp46, retinoblastoma-binding protein p46; Sap30, Sin3A-associated protein, 30 kDa; SDS, serine dehydratase; TBL1X, transducin β-like 1X-linked; TBL1XR1, transducin β-like 1 X-linked receptor 1; GPS2, G protein pathway suppressor 2.