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Review
. 2012 Mar;4(4):505-24.
doi: 10.4155/fmc.12.3.

Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed

Berkley E Gryder  1 , Quaovi H Sodji, Adegboyega K Oyelere
Affiliations
Review

Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed

Berkley E Gryder et al. Future Med Chem. 2012 Mar.

Erratum in

  • Future Med Chem. 2012 Jun;4(10):1369-70

Abstract

Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis - SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution.

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Figures

Figure 1
Figure 1
Factors influencing epigenetic regulation of DNA information.
Figure 2
Figure 2. The dynamic change in histone acetylation states and the accessability of the gene code is facilitated by the activities of two functionally opposed enzymes – histone acetyl transferase and histone deacetylase
Acetylated lysines on core histone tails encourage gene expression via (A) reduction of electrostatic interaction between histone lysines and the DNA phosphate backbone, and also by (B) enabling binding of chromatin reader complexes, such as BPTF, equipped with an acetylated lysine reader (bromo, the bromodomain) and a methylated lysine reader (PHD) [145]. Inhibiting HDACs in the nucleus induces apoptosis via re-establishing expression of key tumor suppressor proteins, such as p53 and p21(Cip1/WAF1) [94]. BPTF: Bromodomain plant homeodomain finger transcription factor; HAT: Histone acetyl transferase; HDAC: Histone deacetlyase; HDACi: Histone deacetlyase inhibitor; PHD: Plant homeodomain.
Figure 3
Figure 3. Various classes of histone deacetylase inhibitors
HDACi: Histone deacetylase inhibitor; SAHA: Suberoylanilide hydroxamic acid.
Figure 4
Figure 4. Histone deacetylase 3 pharmacophoric model for Zn2+-chelating inhibitors
The crystal structure shown highlights the surface (blue), hydrophobic tunnel (gray) and zinc-sequestering active site (red). Each histone deacetylase inhibitor pharmacophore is color-coded to reflect its binding within the histone deacetylase enzyme active site.
Figure 5
Figure 5. Clinical timeline: the explosion of histone deacetylase inhibitor cancer clinical trials, over 490 to date
Count was compiled from the clinicaltrials.gov databank. Numbers for 2010 and 2011 are incomplete given the time lag between start date and appearance in the databank, and do not reflect a decrease in medical excitement surrounding histone deacetylase inhibitors. SAHA: Suberoylanilide hydroxamic acid.
Figure 6
Figure 6. Overcoming clinical roadblocks to histone deacetylase inhibitor cancer therapy
HDACi: Histone deacetylase inhibitor.
Figure 7
Figure 7. Pan histone deacetylase inhibitors
(A) Traditional, non-selective inhibitors (SAHA and TSA data averaged from four independent groups) [43,88,99,109]. (B) Pandacostat, profiled against values calculated from Ki reported by the traditional inhibitors SAHA, TSA and LAQ-824 (IC50 Bradner et al. using the Cheng–Prusoff equation) [19]. HDAC: Histone deacetylase; SAHA: Suberoylanilide hydroxamic acid; TSA: Trichostatin A.
Figure 8
Figure 8. Histone deacetylase isoform selectivity of clinically relevant benzamides and depsipeptide histone deacetylase inhibitors relative to suberoylanilide hydroxamic acid
(A) Clinically relevant benzamide HDACi are selective for HDAC 1,2 and 3 of Class 1, but not HDAC8. (B) Depsipeptide HDACi are selective for Class 1 HDAC and more potent than the benzamides and SAHA. (C) Crystal structure of largazolethiol, the product of in vivo hydrolysis of the thioester bond, bound to HDAC8 shows extensive interaction of the macrocycle with HDAC outer surface rims which may explain the enhanced potency of depsipeptides relative to other HDACis [104]. HDAC: Histone deacetlyase; HDACi; Histone deacetylase inhibitor.
Figure 9
Figure 9
Histone deacetylase 6-selective inhibitors.
Figure 10
Figure 10. Histone deacetylase 8-selective inhibitors
(A) Hydrazide aryl hydroximatic acids and (B) (R)-α-amino-ketones. SAHA: Suberoylanilide hydroxamic acid; TSA: Trichostatin A.
Figure 11
Figure 11. Lung selective distribution profile of clarithromycin and azithromycin in human patients [135]
Lung AV: Lung aveolar macrophage.
Figure 12
Figure 12. Targeted histone deacetylase inhibitor with non-peptide macrocyclic cap groups
(A) Targeting with the cap group from the traditional HDACi pharmacophoric model. (B) Linker length dependance on the activity of non-pepide macrolide HDACi. AO-AZ#: Azithromycin-triazole-HDACi of chain length #n; AO-AZH#: Azithromycin-triazole-HDACi of chain length #n with H replacing the cladinose sugar; AO-CL#: Clarithromycin-triazole-HDACi of chain length #n; AO-CLH#: Clarithromycin-triazole-HDACi of chain length #n with H replacing the cladinose sugar; AO-TK#: Triketolide-triazole-HDACi of chain length #n; AZH: Azithromycin; HDACi: Histone deacetylase inhibitor.
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