3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition

Abstract

Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitor (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative non-hydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 nM and 3675 nM respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.

Drugging the HDAC6–HSP90 interplay in malignant cells

“…Combination with a tolyl linker, Nbonded a,b-unsaturated, or aromatic substituents greatly enhanced activity and selectivity [2,14]. Concerns about pharmacokinetic properties of the HA moiety stimulated scientists to find alternative zinc binding groups (ZBGs) [24]. Thiols, a-ketoesters, electrophilic ketones, mercaptoamides and phosphonates, and 3-hydroxypyridin-2-thione ( Figure 2) are novel ZBGs for selective HDAC6 inhibition in the submicromolar range [24].…”

“…Concerns about pharmacokinetic properties of the HA moiety stimulated scientists to find alternative zinc binding groups (ZBGs) [24]. Thiols, a-ketoesters, electrophilic ketones, mercaptoamides and phosphonates, and 3-hydroxypyridin-2-thione ( Figure 2) are novel ZBGs for selective HDAC6 inhibition in the submicromolar range [24]. Intriguingly, potent and selective inhibition of HDAC6 in the nanomolar range by a 'capless' small molecule inhibitor is possible [25].…”

The antileishmanial activity of isoforms 6- and 8-selective histone deacetylase inhibitors

“…24 We observed that aryl- and diaryl-analogs of these 3HPT-derived HDACi have selective inhibitory activity against HDAC6 or HDAC8 but are otherwise inactive against HDAC1. We envisioned that these 3HPT-derived compounds could constitute useful molecular probes for parsing out the contribution of inhibition of classes I and II HDACs to the antileishmanial activity of HDACi.…”

Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia

“…Recent reports of 3-hydroxypyridine-2-thiones as selective HDAC inhibitors against HDAC 6 and 8 but not HDAC 1 further motivate the disclosure of our study. 25,26 Previously reported 1HPT analogues 24 with single amino acid (1-2) and their synthetic precursor (1HPT-6-carboxilic acid, 3)…”