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Title: Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation

Abstract

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability ofmore » this therapeutic approach. Here, this discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2] more »;  [2];  [2];  [2];  [2] « less
  1. Janssen Research and Development, LLC, Spring House, PA (United States); Yumanity Therapeutics, Cambridge, MA (United States)
  2. Janssen Research and Development, LLC, Spring House, PA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1510227
Grant/Contract Number:  
[AC02-06CH11357]
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
[ Journal Volume: 292; Journal Issue: 43]; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; allosteric regulation; drug action; drug discovery; enzyme inhibitor; enzyme processing; matrix metalloproteinase (MMP); pharmacology

Citation Formats

Scannevin, Robert H., Alexander, Richard, Haarlander, Tara Mezzasalma, Burke, Sharon L., Singer, Monica, Huo, Cuifen, Zhang, Yue-Mei, Maguire, Diane, Spurlino, John, Deckman, Ingrid, Carroll, Karen I., Lewandowski, Frank, Devine, Eric, Dzordzorme, Keli, Tounge, Brett, Milligan, Cindy, Bayoumy, Shariff, Williams, Robyn, Schalk-Hihi, Celine, Leonard, Kristi, Jackson, Paul, Todd, Matthew, Kuo, Lawrence C., and Rhodes, Kenneth J. Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation. United States: N. p., 2017. Web. doi:10.1074/jbc.M117.806075.
Scannevin, Robert H., Alexander, Richard, Haarlander, Tara Mezzasalma, Burke, Sharon L., Singer, Monica, Huo, Cuifen, Zhang, Yue-Mei, Maguire, Diane, Spurlino, John, Deckman, Ingrid, Carroll, Karen I., Lewandowski, Frank, Devine, Eric, Dzordzorme, Keli, Tounge, Brett, Milligan, Cindy, Bayoumy, Shariff, Williams, Robyn, Schalk-Hihi, Celine, Leonard, Kristi, Jackson, Paul, Todd, Matthew, Kuo, Lawrence C., & Rhodes, Kenneth J. Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation. United States. doi:10.1074/jbc.M117.806075.
Scannevin, Robert H., Alexander, Richard, Haarlander, Tara Mezzasalma, Burke, Sharon L., Singer, Monica, Huo, Cuifen, Zhang, Yue-Mei, Maguire, Diane, Spurlino, John, Deckman, Ingrid, Carroll, Karen I., Lewandowski, Frank, Devine, Eric, Dzordzorme, Keli, Tounge, Brett, Milligan, Cindy, Bayoumy, Shariff, Williams, Robyn, Schalk-Hihi, Celine, Leonard, Kristi, Jackson, Paul, Todd, Matthew, Kuo, Lawrence C., and Rhodes, Kenneth J. Thu . "Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation". United States. doi:10.1074/jbc.M117.806075. https://www.osti.gov/servlets/purl/1510227.
@article{osti_1510227,
title = {Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation},
author = {Scannevin, Robert H. and Alexander, Richard and Haarlander, Tara Mezzasalma and Burke, Sharon L. and Singer, Monica and Huo, Cuifen and Zhang, Yue-Mei and Maguire, Diane and Spurlino, John and Deckman, Ingrid and Carroll, Karen I. and Lewandowski, Frank and Devine, Eric and Dzordzorme, Keli and Tounge, Brett and Milligan, Cindy and Bayoumy, Shariff and Williams, Robyn and Schalk-Hihi, Celine and Leonard, Kristi and Jackson, Paul and Todd, Matthew and Kuo, Lawrence C. and Rhodes, Kenneth J.},
abstractNote = {Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. Here, this discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.},
doi = {10.1074/jbc.M117.806075},
journal = {Journal of Biological Chemistry},
number = [43],
volume = [292],
place = {United States},
year = {2017},
month = {8}
}

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Works referenced in this record:

Novel MT1-MMP Small-Molecule Inhibitors Based on Insights into Hemopexin Domain Function in Tumor Growth
journal, March 2012


Structural and functional bases for allosteric control of MMP activities: Can it pave the path for selective inhibition?
journal, January 2010

  • Sela-Passwell, Netta; Rosenblum, Gabriel; Shoham, Tsipi
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1803, Issue 1
  • DOI: 10.1016/j.bbamcr.2009.04.010

Discovery and Evaluation of a Non-Zn Chelating, Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitor for Potential Intra-articular Treatment of Osteoarthritis
journal, January 2012

  • Gege, Christian; Bao, Bagna; Bluhm, Harald
  • Journal of Medicinal Chemistry, Vol. 55, Issue 2
  • DOI: 10.1021/jm201152u

Structural Basis for the Highly Selective Inhibition of MMP-13
journal, February 2005


Binding of Active (57 kDa) Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) to Tissue Inhibitor of Metalloproteinase (TIMP)-2 Regulates MT1-MMP Processing and Pro-MMP-2 Activation
journal, April 2000

  • Hernandez-Barrantes, Sonia; Toth, Marta; Bernardo, M. Margarida
  • Journal of Biological Chemistry, Vol. 275, Issue 16
  • DOI: 10.1074/jbc.275.16.12080

The finer things in X-ray diffraction data collection
journal, October 1999

  • Pflugrath, J. W.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 55, Issue 10
  • DOI: 10.1107/S090744499900935X

Doxycycline inhibits neutrophil (PMN)-type matrix metalloproteinases in human adult periodontitis gingiva
journal, February 1995


Activation of Matrix Metalloproteinase-9 (MMP-9) via a Converging Plasmin/Stromelysin-1 Cascade Enhances Tumor Cell Invasion
journal, May 1999

  • Ramos-DeSimone, Noemi; Hahn-Dantona, Elizabeth; Sipley, John
  • Journal of Biological Chemistry, Vol. 274, Issue 19
  • DOI: 10.1074/jbc.274.19.13066

Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase
journal, June 2002

  • Elkins, Patricia A.; Ho, Yen Sen; Smith, Ward W.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 7
  • DOI: 10.1107/S0907444902007849

Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases
journal, May 2003

  • Power, Christopher; Henry, Scot; Del Bigio, Marc R.
  • Annals of Neurology, Vol. 53, Issue 6
  • DOI: 10.1002/ana.10553

Rapid automated molecular replacement by evolutionary search
journal, February 1999

  • Kissinger, Charles R.; Gehlhaar, Daniel K.; Fogel, David B.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 55, Issue 2
  • DOI: 10.1107/S0907444998012517

Effects of Matrix Metalloproteinase-9 Gene Knock-Out on Morphological and Motor Outcomes after Traumatic Brain Injury
journal, September 2000


Mechanism Of Cell Surface Activation Of 72-kDa Type IV Collagenase: ISOLATION OF THE ACTIVATED FORM OF THE MEMBRANE METALLOPROTEASE
journal, March 1995

  • Strongin, Alex Y.; Collier, Ivan; Bannikov, Gregory
  • Journal of Biological Chemistry, Vol. 270, Issue 10
  • DOI: 10.1074/jbc.270.10.5331

Control of matrix metalloproteinase catalytic activity
journal, October 2007


Early appearance of activated matrix metalloproteinase-9 and blood–brain barrier disruption in mice after focal cerebral ischemia and reperfusion
journal, September 1999


The Design, Structure, and Clinical Update of Small Molecular Weight Matrix Metalloproteinase Inhibitors
journal, November 2004

  • Skiles, Jerry; Gonnella, Nina; Jeng, Arco
  • Current Medicinal Chemistry, Vol. 11, Issue 22
  • DOI: 10.2174/0929867043364018

Metalloproteinase increases in the injured rat spinal cord
journal, January 2000


Urokinase directly activates matrix metalloproteinases-9: A potential role in glioblastoma invasion
journal, May 2008

  • Zhao, Yunge; Lyons, Charles E.; Xiao, Aizhen
  • Biochemical and Biophysical Research Communications, Vol. 369, Issue 4
  • DOI: 10.1016/j.bbrc.2008.03.038

Increased Matrix Metalloproteinase-9 in Blood in Association with Activation of Interleukin-6 after Traumatic Brain Injury: Influence of Hypothermic Therapy
journal, December 2004

  • Suehiro, Eiichi; Fujisawa, Hirosuke; Akimura, Tatsuo
  • Journal of Neurotrauma, Vol. 21, Issue 12
  • DOI: 10.1089/neu.2004.21.1706

Astrocytic Induction of Matrix Metalloproteinase-9 and Edema in Brain Hemorrhage
journal, June 2006

  • Tejima, Emiri; Zhao, Bing-Qiao; Tsuji, Kiyoshi
  • Journal of Cerebral Blood Flow & Metabolism, Vol. 27, Issue 3
  • DOI: 10.1038/sj.jcbfm.9600354

Matrix Metalloproteinases as Valid Clinical Target
journal, January 2007


Unraveling Hidden Regulatory Sites in Structurally Homologous Metalloproteases
journal, July 2013


Peptide Inhibition of Catalytic and Noncatalytic Activities of Matrix Metalloproteinase-9 Blocks Tumor Cell Migration and Invasion
journal, April 2004

  • Björklund, Mikael; Heikkilä, Pia; Koivunen, Erkki
  • Journal of Biological Chemistry, Vol. 279, Issue 28
  • DOI: 10.1074/jbc.M401601200

Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases.
journal, December 1994

  • Gijbels, K.; Galardy, R. E.; Steinman, L.
  • Journal of Clinical Investigation, Vol. 94, Issue 6
  • DOI: 10.1172/JCI117578

Matrix metalloproteinases and the regulation of tissue remodelling
journal, March 2007

  • Page-McCaw, Andrea; Ewald, Andrew J.; Werb, Zena
  • Nature Reviews Molecular Cell Biology, Vol. 8, Issue 3
  • DOI: 10.1038/nrm2125

Universal Screening Methods and Applications of ThermoFluor®
journal, October 2006

  • Cummings, Maxwell D.; Farnum, Michael A.; Nelen, Marina I.
  • Journal of Biomolecular Screening, Vol. 11, Issue 7
  • DOI: 10.1177/1087057106292746

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis
journal, January 2010

  • Schnute, Mark E.; O’Brien, Patrick M.; Nahra, Joe
  • Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 2
  • DOI: 10.1016/j.bmcl.2009.11.081

Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions
journal, December 1997

  • Cossins, Judy A.; Clements, John M.; Ford, Janice
  • Acta Neuropathologica, Vol. 94, Issue 6
  • DOI: 10.1007/s004010050754

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors
journal, April 2002

  • Maquoi, Erik; Munaut, Carine; Colige, Alain
  • Experimental Cell Research, Vol. 275, Issue 1
  • DOI: 10.1006/excr.2002.5489

Crystal Structure of Human MMP9 in Complex with a Reverse Hydroxamate Inhibitor
journal, May 2002


Generation and Characterization of Subtype-specific Monoclonal Antibodies to K + Channel α- and β-subunit Polypeptides
journal, January 1996


MMP-Related Gelatinase Activity Is Strongly Induced in Scar Tissue of Injured Adult Spinal Cord and Forms Pathways for Ingrowing Neurites
journal, June 2001

  • Duchossoy, Yann; Horvat, Jean-Claude; Stettler, Olivier
  • Molecular and Cellular Neuroscience, Vol. 17, Issue 6
  • DOI: 10.1006/mcne.2001.0986

An Integrated Computational and Experimental Approach to Gaining Selectivity for MMP-2 within the Gelatinase Subfamily
journal, January 2014


Human matrix metalloproteinase-9 : activation by limited trypsin treatment and generation of monoclonal antibodies specific for the activated form
journal, November 1998


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family
journal, January 2015

  • Zapico, José María; Puckowska, Anna; Filipiak, Kamila
  • Organic & Biomolecular Chemistry, Vol. 13, Issue 1
  • DOI: 10.1039/C4OB01516A

Mechanism of Activation of Human Neutrophil Gelatinase B: DISCRIMINATING BETWEEN THE ROLE OF Ca IN ACTIVATION AND CATALYSIS
journal, August 1995


Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat
journal, July 2006

  • Yang, Yi; Estrada, Eduardo Y.; Thompson, Jeffrey F.
  • Journal of Cerebral Blood Flow & Metabolism, Vol. 27, Issue 4
  • DOI: 10.1038/sj.jcbfm.9600375

Insight into the structural determinants for selective inhibition of matrix metalloproteinases
journal, August 2007


New strategies for targeting matrix metalloproteinases
journal, May 2015


Neuronal Matrix Metalloproteinase-9 Is a Determinant of Selective Neurodegeneration
journal, January 2014


Osler and the “medico-chirurgical neurologists”: Horsley, Cushing, and Penfield
journal, July 2003


Matrix metalloproteinase—9 concentration after spontaneous intracerebral hemorrhage
journal, July 2003


Inhibition of MMP-2 gelatinolysis by targeting exodomain–substrate interactions
journal, July 2007

  • Xu, Xiaoping; Chen, Zhihua; Wang, Yao
  • Biochemical Journal, Vol. 406, Issue 1
  • DOI: 10.1042/BJ20070591