Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer

Abstract

Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.

Keywords: cancer; dual-target therapy; epigenetics; histone deacetylases; inhibitors; kinases; rational design.

Figure 1

The structure of human HDAC6 (above) and danio rerio HDAC6 (below).

Figure 2

(IA) Classical pharmacophore model of HDAC inhibitors; (IB) extended pharmacophore model of HDAC inhibitors; (II) structures of selective HDAC6 inhibitors that are in clinical trials; (III) structures of registered pan-HDAC inhibitors.

Figure 3

Schematic representation of molecular associations and signaling pathways of HDAC6 and other targets.

Figure 4

Development of dual HDAC6/PI3K inhibitors; (I,II)—fusion of pharmacophores of PI3K inhibitors and HDAC6 inhibitors in order to develop HDAC6/PI3K dual inhibitors (CUDC-901 and 1); (III)—Modification of alpelisib structure in order to develop HDAC6/ PI3Kα dual inhibitor—2; (IV)—Modification of duvelisib structure in order to develop HDAC6 PI3Kδ dual inhibitor—3; The zinc-binding groups are highlighted in blue; the PI3K inhibitors’ key structure components are highlighted in green and pink; the CAP group of HDAC inhibitors is highlighted in red; and the solvent-exposed regions are indicated by blue circles.

Figure 5

(I) Basis for rational design of 2: position of alpelisib inside the binding pocket of PI3Kα (left) and 2D diagram of the most important alpelisib–PI3Kα interactions (right); solvent-exposed region is indicated by red circles. (II) Basis for rational design of 3: position of idelalisib inside the binding pocket of PI3Kδ (left) and 2D diagram of the most important idelalisib–PI3Kα interactions (right); the solvent-exposed region is indicated by red circles.

Figure 6

Development of dual HDAC6/mTOR inhibitor. The zinc-binding group is highlighted in blue; the hinge domain is highlighted in green; and the CAP group is highlighted in red.

Figure 7

(I) Basis for rational design of dual HDAC6/BRD4 inhibitor: position of ABBV-744 inside the binding pocket of bromodomain 2 (BD2) (left) and 2D diagram of the most important ABBV744–BD2 interactions (right); the solvent-exposed region is indicated by red circles; (II) Development of dual HDAC6/BRD4 inhibitor: fusion of pharmacophores of BRD4 inhibitor and HDAC6 inhibitor. The zinc-binding group is highlighted in blue; the BRD4 inhibitor’s key structure components are highlighted in green; the CAP group of HDAC inhibitor is highlighted in red; and the solvent-exposed part of ABBV-744 is indicated by a blue circle.

Figure 8

Development of dual HDAC6/AR inhibitor: merger of pharmacophores of AR inhibitor and HDAC6 inhibitor. The zinc-binding group is highlighted in blue; the CAP group is highlighted in red, and the pharmacophore group of AR inhibitor is highlighted green.

Figure 9

Development of dual HDAC6/HSP90 inhibitors. (I) Fusion of pharmacophores of HSP90 inhibitor and HDAC inhibitor. The zinc-binding group is highlighted in blue; the CAP group is highlighted in red; and the HSP90 binding domain is highlighted in green. (II) Modification of AUY922 structure in order to develop HDAC6/HSP90 dual inhibitor—10.

Figure 10

Development of dual HDAC6/tubulin inhibitors: (I)—Modification of SCB01A structure in order to develop HDAC6/tubulin dual inhibitors—11 and 12; (II)—Modification the structure of already known microtubule destabilizer in order to design 13; (III)—Structure of HDAC6/tubulin dual inhibitor (14)The zinc-binding groups are highlighted in blue; the tubulin inhibitors’ key structure components are highlighted in green; the CAP group of HDAC inhibitors is highlighted in red; and the solvent-exposed regions are indicated with blue circles.

Figure 11

Development of dual HDAC6/LSD1 inhibitors: (I)—fusion of pharmacophores of LSD1 inhibitor and HDAC inhibitors in order to develop corin and 15; (II)—Modification of GSK2879552 structure (already known LSD1 inhibitor) in order to develop HDAC6/LSD1 dual inhibitor—16. The zinc-binding groups are highlighted in blue; the CAP groups are highlighted in red; and the critical part of the structure important for LSD1 inhibition is highlighted in green.

Figure 12

The most potent HDAC6/1 inhibitors from each series.

Figure 13

Development of dual HDAC6/HDAC3 inhibitors: fusion of pharmacophores of G9a inhibitor and HDAC inhibitors. The zinc-binding groups are highlighted in blue; the CAP group is highlighted in red; and the pharmacophore of G9a inhibitor is highlighted in green and pink.

Figure 14

The most potent HDAC6/8 inhibitors from each series.

Figure 15

Development of dual HDAC6/PAK1 inhibitors: fusion of pharmacophores of PAK1 inhibitor and HDAC6 inhibitors. The zinc-binding groups are highlighted in blue; the CAP group of HDAC inhibitor is highlighted in red, the hinge domain of PAK1 inhibitor is highlighted in green; and the structure features that interact with hydrophobic pocket are highlighted in purple.

Figure 16

(I) Basis for rational design of dual HDAC6/FAK inhibitor: position of TAE-226 inside the binding pocket of FAK (left) and 2D diagram of the most important TAE-226–FAK interactions (right); the solvent-exposed region is highlighted in red. (II) Development of dual HDAC6/FAK inhibitor: fusion of pharmacophores of FAK inhibitor and HDAC6 inhibitors. The zinc-binding groups are highlighted in blue; the CAP group of HDAC inhibitors is highlighted in red; and the key structural elements important for FAK inhibition are highlighted in green.