title: SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of A Disintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes.
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.
authors.affiliation: ∥Florida Atlantic University, 5353 Parkside Drive, Jupiter, Florida 33458, United States.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Knapinska
authors.affiliation: ⊥Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymuller
authors.affiliation: ⊥Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: ∥Florida Atlantic University, 5353 Parkside Drive, Jupiter, Florida 33458, United States.
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Smith
authors.affiliation: ‡Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Golubkov
authors.affiliation: §Wayne State University, 8200 Scott Hall, 540 East Canfield Avenue, Detroit, Michigan 48201, United States.
authors.forename: Anjum
authors.initials: A
authors.lastname: Sohail
authors.affiliation: §Wayne State University, 8200 Scott Hall, 540 East Canfield Avenue, Detroit, Michigan 48201, United States.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.affiliation: †Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.|∇Department of Chemistry, Center for Drug Discovery and Innovation, University of South Florida, Tampa, Florida 33612, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Giulianotti
authors.affiliation: †Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Travis M
authors.initials: TM
authors.lastname: LaVoi
authors.affiliation: †Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.affiliation: ∥Florida Atlantic University, 5353 Parkside Drive, Jupiter, Florida 33458, United States.|#The Scripps Research Institute/Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
authors.affiliation: †Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Minond
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D015335:Molecular Probes; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D015335:Molecular Probes; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human