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

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

  • J Med Chem. 2015 Aug 13;58(15):5808-24. doi: 10.1021/acs.jmedchem.5b00354.
Anna M Knapinska 1,  Daniela Dreymuller 2,  Andreas Ludwig 2,  Lyndsay Smith 1,  Vladislav Golubkov 3,  Anjum Sohail 4,  Rafael Fridman 4,  Marc Giulianotti 5 6,  Travis M LaVoi 5,  Richard A Houghten 5,  Gregg B Fields 1 7,  Dmitriy Minond 5
Affiliations

Affiliations

  • 1 ∥Florida Atlantic University, 5353 Parkside Drive, Jupiter, Florida 33458, United States.
  • 2 ⊥Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany.
  • 3 ‡Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
  • 4 §Wayne State University, 8200 Scott Hall, 540 East Canfield Avenue, Detroit, Michigan 48201, United States.
  • 5 †Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
  • 6 ∇Department of Chemistry, Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33612, United States.
  • 7 #The Scripps Research Institute/Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, United States.
PMID: 26192023 DOI: 10.1021/acs.jmedchem.5b00354
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.

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