The Zinc-Binding Group Effect: Lessons from Non-Hydroxamic Acid Vorinostat Analogs

Abstract

Histone deacetylases (HDACs) are enzymes pursued as drug targets in various cancers and several non-oncological conditions, such as inflammation and neurodegenerative disorders. In the past decade, HDAC inhibitors (HDACi) have emerged as relevant pharmaceuticals, with many efforts devoted to the development of new representatives. However, the growing safety concerns regarding the established hydrox­amic acid-based HDAC inhibitors tend to drive current research more toward the design of inhibitors bearing alternative zinc-binding groups (ZBGs). This Perspective presents an overview of all non-hydrox­amic acid ZBGs that have been incorporated into the clinically approved prototypical HDACi, suberoyl­anilide hydrox­amic acid (vorinostat). This provides the unique opportunity to compare the inhibition potential and biological effects of different ZBGs in a direct way, as the compounds selected for this Perspective differ only in their ZBG. To that end, different strategies used to select a ZBG, its properties, activity, and liabilities are discussed.

Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

“…[ 33–35 ] Therefore, substantial effort was expended on the development of alternative or novel ZBGs to replace the traditional ZBGs in HDAC inhibitors while retaining their potency. [ 36–38 ] Interestingly, nonhydroxamate ZBGs are typically less potent than the most popular hydroxamates, but they could exhibit greater selectivity among isoforms of HDACs and might be less toxic, which might suggest their long‐term use in the treatment of other nonlethal diseases. [ 38,39 ]…”

Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism

“…For HAs, the major elimination pathway in rodents and a significant elimination pathway in humans is phase II glucuronidation. The properties of the HA, therefore, often result in unfavorable in vivo pharmacokinetic (PK) profiles with rapid clearance rates and short half-lives, which may result in suboptimal drug exposure. , In addition, the main metabolite of HA-containing compounds is the corresponding carboxylic acid, with a high probability of forming unstable glucuronides that could cause drug-induced liver injury (DILI). , Furthermore, several HAs have been shown to be mutagenic, likely through a mechanism involving a Lossen rearrangement, leading to highly reactive isocyanates. ,, The search for selective and nontoxic HDAC6 inhibitors for chronic treatment of indications outside of oncology has prompted increased efforts to find inhibitors with alternative non-HA zinc-binding groups (ZBGs). ,− …”

Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple‐Negative Breast Cancer

“…[19] Most HDAC inhibitors can be characterized by a general pharmacophore model with three components: a zinc binding group (ZBG, pink shading in Figure 1b) for chelation to the active site zinc ion, a linker that traverses the tunnel leading to the active site, and a surface recognition cap group protruding beyond the substrate binding channel and engaging in additional binding interactions with the rim of the enzyme. [20] Thereinto, chelation of the zinc ion has proven to be critical for HDAC inhibition. The flexibility of cap group preference provided medicinal chemists with freedom to operate and design structurally divergent HDAC inhibitors.…”