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.

Figure 1. The molecular targets of HDACs, downstream cellular pathways, and anticancer outcomes of HDAC inhibition.

HDAC substrates include histones and nonhistone proteins. Histones are the primary substrates for HDAC1, -2, and -3, while other cellular proteins are targeted by one or more class I and class II HDACs. Some known HDAC targets, downstream molecular changes that occur following HDAC inhibition, and associated biological pathways that mediate antitumor responses are shown. The HDACs, substrates, and molecular responses are color matched to illustrate functional relationships. The best-characterized biological consequences of HDACi treatment of tumor cells are shown on the lowest tier of the diagram. SMC3, structural maintenance of chromosomes 3; GCMa, glial cells missing homolog 1; HAT, histone acetyltransferase; HP1, heterochromatin protein 1.

Figure 2. The specificity of HDACis for HDACs and associated protein complexes.

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 K_D^app 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.