Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6

Abstract

Little is known about the biological and structural features that govern the isoform selectivity for class I histone deacetylases (HDACs) over HDAC6. In addition to that for known inhibitors, like benzamides, psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was also observed for naturally occurring cyclopeptide HDAC inhibitors with an aliphatic flexible linker and ketonelike zinc-binding group (ZBG). The present study reports that this isoform selectivity is mainly due to the linker and ZBG, as replacement of the cyclopeptide cap region by a simple aniline retained class I HDAC isoform selectivity toward HDAC6 in enzymatic assays. The best cyclopeptide-free analogues preserved efficacy against Plasmodium falciparum and cancer cell lines. Molecular modeling provided hypotheses to explain this selectivity and suggests different behaviors of the flexible linker on HDAC1 and HDAC6 pockets, which may influence, on the basis of the strength of the ZBG, its coordination with the zinc ion.

Methods for addressing the protein-protein interaction between histone deacetylase 6 and ubiquitin

“…In addition to the positive binding control mono-Ub (ZnF-UBP-positive/catalytic-negative), the selective HDAC6 inhibitor tubastatin A (ZnF-UBP-negative/catalytic-positive binding control) and a class I-selective hydroxyl ketone inhibitor (HKI, ZnF-UBP-negative/catalytic-negative binding control, Fig. S6) 14 were probed.…”

“…Yung-Sing Wong. 15 All compounds screened for ZnF-UBP-Ub modulation were purchased from the Specs company (http//www.specs.net).…”

“…2b).Unfortunately, MST experiments to determine the K D for the binding between compound 16 and HDAC6-EGFP WT could not be performed because of the strong intrinsic fluorescence displayed by the ligand at concentrations higher than 100 µM.In addition to the positive binding control mono-Ub (ZnF-UBP-site positive, catalytic-site negative), the selective HDAC6 inhibitor tubastatin A (ZnF-UBP-site negative, catalytic-site positive 6 binding control) and a HDAC class I-selective hydroxyl ketone inhibitor (HKI; ZnF-UBP-site negative, catalytic-site negative binding control, Fig. S6) 15 were probed. Binding of HDAC6 catalytic inhibitors to the full-length HDAC6 could be detected in both thermophoresis alone and thermophoresis + T-Jump experiments (Fig.…”

Discovery of N-(2-Amino-4-Fluorophenyl)-4-[bis-(2-Chloroethyl)-Amino]-Benzamide as a Potent HDAC3 Inhibitor

“…Chidamide (CS055) was approved by the Chinese Food and Drug Administration for the treatment of PTCL ( 34 ). Generally, pharmacophores of HDACIs are consist of three structural elements: a capping group, which recognizes the hydrophobic region at the opening of HDAC active site; a linker, which connects the hydrophobic ring and the zinc-binding group (ZBG) via occupation of the tubular channel; a ZBG, whose functions include binding to the zinc ion located in the active center of HDACs, as well as forming hydrogen bonds with certain amino acid residues of active sites ( 35 – 37 ).…”

Design, Synthesis and Cytotoxicity Study of Primary Amides as Histone Deacetylase Inhibitors

“…These three classes have a zinc-dependent catalytic site. The rest seven isoforms depend on the cofactor nicotine adenine dinucleotide rather than zinc for their catalytic activity and comprise class III (6) .…”