1 research outputs found
3‑Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition
Small
molecules bearing hydroxamic acid as the zinc binding group
(ZBG) have been the most effective histone deacetylase inhibitors
(HDACi) to date. However, concerns about the pharmacokinetic liabilities
of the hydroxamic acid moiety have stimulated research efforts aimed
at finding alternative nonhydroxamate 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 IC<sub>50</sub> of 681 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