SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of A Disintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes

ADAM17
is implicated in several debilitating diseases. However,
drug discovery efforts targeting ADAM17 have failed due to the utilization
of zinc-binding inhibitors. We previously reported discovery of highly
selective nonzinc-binding exosite-targeting inhibitors of ADAM17 that
exhibited not only enzyme isoform selectivity but synthetic substrate
selectivity as well (J.
Biol. Chem. 2013, 288, 22871). As a result of SAR studies presented herein,
we obtained several highly selective ADAM17 inhibitors, six of which
were further characterized in biochemical and cell-based assays. Lead
compounds exhibited low cellular toxicity and high potency and selectivity
for ADAM17. In addition, several of the leads inhibited ADAM17 in
a substrate-selective manner, which has not been previously documented
for inhibitors of the ADAM family. These findings suggest that targeting
exosites of ADAM17 can be used to obtain highly desirable substrate-selective
inhibitors. Additionally, current inhibitors can be used as probes
of biological activity of ADAM17 in various in vitro and, potentially,
in vivo systems.