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

Journal Article · · Journal of Biological Chemistry
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  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)
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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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1510227
Journal Information:
Journal of Biological Chemistry, Vol. 292, Issue 43; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 88 works
Citation information provided by
Web of Science

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Cited By (11)

The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma journal August 2019
Recent insights into natural product inhibitors of matrix metalloproteinases journal January 2019
Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases journal November 2018
Propeptide glycosylation and galectin‐3 binding decrease proteolytic activation of human pro MMP ‐9/progelatinase B journal November 2018
SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice journal December 2019
Mechanisms of Action of Novel Drugs Targeting Angiogenesis-Promoting Matrix Metalloproteinases journal June 2019
Metalloproteinases TACE and MMP-9 Differentially Regulate Death Factors on Adult and Neonatal Monocytes After Infection with Escherichia coli journal March 2019
Proteases: Pivot Points in Functional Proteomics book October 2018
Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets journal April 2019
Targeting Tumor Microenvironment for Cancer Therapy journal February 2019
MMP2 as an independent prognostic stratifier in oral cavity cancers journal January 2020

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Related Subjects

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