4 research outputs found
ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors
A systematic study of medicinal chemistry
aimed at identifying
a new generation of HDAC inhibitors, through the introduction of a
thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position
of the polyethylene chain of the vorinostat scaffold, allowed the
selection of a new class of potent pan-HDAC inhibitors (pan-HDACis).
Simple, highly versatile, and efficient synthetic approaches were
used to synthesize a library of these new derivatives, which were
then submitted to a screening for HDAC inhibition as well as to a
preliminary in vitro assessment of their antiproliferative activity.
Molecular docking into HDAC crystal structures suggested a binding
mode for these thiol derivatives consistent with the stereoselectivity
observed upon insertion of amide-lactam substituents in the ω-position.
ST7612AA1 (<b>117</b>), selected as a drug candidate for further
development, showed an in vitro activity in the nanomolar range associated
with a remarkable in vivo antitumor activity, highly competitive with
the most potent HDAC inhibitors, currently under clinical trials.
A preliminary study of PK and metabolism is also illustrated