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

Histone deacetylase 6 (HDAC6) is a unique member of the
HDAC family
mainly targeting cytosolic non­histone substrates, such as α-tubulin,
cortactin, and heat shock protein 90 to regulate cell proliferation,
metastasis, invasion, and mitosis in tumors. We describe the identification
and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles
(DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing
structure–activity relationships and performing quantum mechanical
calculations of the HDAC6 catalytic mechanism, we show that potent
oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism
for the bioactivation. We also observe that the inherent electrophilicity
of the oxadiazoles makes them prone to degradation in water solution
and the generation of potentially toxic products cannot be ruled out,
limiting the developability for chronic diseases. However, the oxadiazoles
demonstrate high oral bioavailability and low in vivo clearance and
are excellent tools for studying the role of HDAC6 in vitro and in
vivo in rats and mice.