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

Knapinska, AM, Dreymuller, D, Ludwig, A et al. (2015). SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of A Disintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes . JOURNAL OF MEDICINAL CHEMISTRY, 58(15), 5808-5824. 10.1021/acs.jmedchem.5b00354

cited authors

  • Knapinska, AM; Dreymuller, D; Ludwig, A; Smith, L; Golubkov, V; Sohail, A; Fridman, R; Giulianotti, M; Lavoi, TM; Houghten, RA; Fields, GB; Minond, D

abstract

  • 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.

publication date

  • July 20, 2015

published in

Digital Object Identifier (DOI)

start page

  • 5808

end page

  • 5824

volume

  • 58

issue

  • 15