Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8

Abstract

Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, neurodegenerative, immunological, and anti-parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8.

In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

“…A mode of binding having bidentate coordination of the Zn 2+ atom with the hydroxamate tail was produced, which is consistent with crystal structures of other hydroxamic acid HDAC inhibitors [2,21,23,24]. Similar to panobinostat, the cyclopropane derivatives were shown to be able to participate in π-π stacking interactions within the core of the active site between the residues Phe-812 and Phe-871 lining the gorge [25]. The benzene ring was shown to be positioned within the LSP of HDAC4.…”

“…The benzene core of panobinostat can participate in π-π stacking interactions with the Phe-Phe motif, while vorinostat having a purely aliphatic linker region cannot. Currently, the inclusion of heteroaromatic rings used in hydroxamic acid derivatives for HDAC inhibitors development has also been evaluated [16,21,22,25]. In studies focused on HDAC4, tandem aromatic rings cores have also been explored, evaluating ring systems combining either two 6-membered aromatic rings, or an aromatic 6-membered and aromatic 5-membered bound to each other [16,21,22].…”

“…The influence of heteroatom inclusion in the innermost ring (ring which is directly attached to the cyclopropane ring) has not been explored. A heteroaromatic ring in the innermost position might allow for more hydrogen bonding interactions with the histidineresidues in the active site [25]. Thus, derivatives of compounds 22, 25, 30, and 31 (Supplementary Figure S4) were designed to determine the impact of heteroatom inclusion in the innermost ring of cyclopropane derivatives on HDAC4 inhibitor potency.…”

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

“…Despite advances in Class I HDAC inhibition, there remains an obvious need to develop compounds having better therapeutic properties as a single-agent therapeutic drug. Our recent research based on computational studies indicated heterocyclic cores as suitable surrogates for the central core of the hydroxamate derivative, panobinostat [12]. It should be noted that TOI3-rev in this article is different from TOI3 in the previous reporting [12].…”

“…Our recent research based on computational studies indicated heterocyclic cores as suitable surrogates for the central core of the hydroxamate derivative, panobinostat [12]. It should be noted that TOI3-rev in this article is different from TOI3 in the previous reporting [12]. Here, the 1,2-diazole ring has been replaced with that of a pyrimidine core.…”