Strategies To Design Selective Histone Deacetylase Inhibitors

Abstract

This review classifies drug‐design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure‐activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class‐specific sub‐pockets: the side‐pocket‐, lower‐pocket‐ and foot‐pocket‐targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

“…Non-hydroxamate ZBGs are usually less potent than hydroxamates, but they can exhibit greater selectivity among isoforms and are potentially less toxic, which might implicate long-term therapeutic use for other non-life-threatening diseases [ 41 ]. The aspect of isozyme selectivity was treated in great detail in the excellent recent reviews by Ho et al [ 10 ] and Melesina et al [ 42 ], which are recommended for further reading. In this review, we address the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present.…”

Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation

“…Regarding HDAC inhibitors, they all present a Zinc-Binding Group (ZBG) a linker and a cap group (CG). The ZBG targets the catalytic zinc ion, while the linker establishes interactions with the amino acids lining the sides of the access tunnel to that ion; and, the cap group interacts with the surface of the protein [ 171 ]. Despite the difficulties for achieving selectivity derived by the homology between HDAC family members, different structural modifications to the basic ZBG-linker-CG have proven to be useful for selective targeting of the different HDACs, as has been gathered by Melesina J. et al in their review on HDAC inhibitors [ 171 ].…”

“…However, despite the amount of described HDACis, only a few have been used as POI ligands in the design of HDAC targeted PROTACs: Nexturastat A ® (potent and selective HDAC6 inhibitor [ 171 ]), Crebinostat ® (pan-HDACi) [ 75 ], CI-994, and SR-3558 (Class I HDAC inhibitors) [ 165 ]. The design of PROTAC I ( Figure 13 ) using the pan-HDAC inhibitor crebinostat and pomalidomide resulted in a selective reduction in the cellular levels of HDAC6 at 80 nM concentrations in MM.1S cells [ 38 , 75 , 168 ], and in a dose-dependent manner, where the optimal effect was found at concentrations ranging from 123 nM to 370 nM in MCF-7 cells [ 38 , 168 ].…”

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

“…As a result, there are significant variations among HDACs’ selectivity ( Table 1 ), which seems to stem from their chemical nature. For instance, in HDAC6, the entrance area on the enzyme’s surface is larger compared to other isoforms, and therefore selectivity for this enzyme has been achieved by incorporating large cap groups and benzyl linkers instead of aliphatic chains [ 30 ]. Selectivity of compounds across HDACs has been determined primarily through cell-free enzymatic activity assays of HDAC1, HDAC2, HDAC3, and HDAC6; and only few studies have tested all enzymes [ 10 , 11 , 12 , 13 , 15 , 16 , 17 , 18 ].…”