Targeting histone deacetylases for cancer therapy: Trends and challenges

Abstract

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

Keywords: Combination therapy; HDACs; Multitarget agent; Oncogenesis; PROTAC; Selective inhibitor.

Graphical abstract

Figure 1

The regulation of gene transcription mediated by HDACs and HATs.

Figure 2

Schematic depiction of HDAC isoforms. Catalytic domains are shown as bright blue column (zinc-dependent HDACs) and green column (NAD⁺-dependent HDACs).

Figure 3

A schematic view of HDACs biological functions. (a) Nuclear export of HMGB1; (b) Bax translocation and the intrinsic apoptosis; (c) Degradation of misfolded protein; (d) STAT3 nuclear translocation; (e) Cell motility and migration; (f) The acetylation and function of importin; (g) p53 protein stability; (h) Association of transcription factors with DNA.

Figure 4

The role of HDACs in cancer pathogenesis.

Figure 5

The intrinsic apoptotic pathway regulated by HDACs.

Figure 6

Chemical structures, HDACs inhibitory activities of approved HDACis and clinical candidate HDACis^,, , , .

Figure 7

The therapeutic effects of vorinostat against solid tumors and hematomas.

Figure 8

Schematic view of different HDAC isoform structures with selective inhibitors.

Figure 9

Examples of HDAC1 and HDAC2 selective inhibitors.

Figure 10

Examples of HDAC3 selective inhibitors.

Figure 11

Examples of HDAC6 selective inhibitors.

Figure 12

Examples of HDAC8 selective inhibitors.

Figure 13

Examples of HDAC10 and HDAC11 selective inhibitors.

Figure 14

Examples of class IIa HDACs selective inhibitors.

Figure 15

Examples of HDAC dual selective inhibitors.

Figure 16

Promising synergistic targets with HDACs.

Figure 17

Examples of PROTACs 39–41.

Figure 18

Examples of PROTACs 42–44.

Figure 19

Examples of PROTACs 45–49.

Figure 20

Examples of PROTACs 50–51.