ArticleThe Journal of biological chemistry2017
Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 171 citations in OpenAlex.
- Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1).Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Trial
- Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets.The Journal of clinical investigation · 2019Trial
- A review on MMP-2 modulating agents from natural and synthetic sources and their role in inflammatory bowel disease.Inflammopharmacology · 2026Review
- Actin polymerization drives endogenous MMP-9 upregulation and blood-brain barrier disruption in ischemic brain endothelial cells.Molecular and cellular biochemistry · 2026Article
- Unraveling the Anti-Arthritic Potential of Bioactive Compounds FromFood science & nutrition · 2026Article
- Kinetic and inhibitory profiling of serum MMP-9 in acute spinal cord injury: neurochemical links to injury severity and neuroinflammation.Acta neurologica Belgica · 2026Article
- The JNJ0966 Significantly Reduces the Elevated Serum MMP-9 and Blood Pressure Observed in SHRs With Periodontitis.International dental journal · 2026Article
- Therapeutic potential of inhibitors of gelatinases MMP-2 and MMP-9 for the treatment of breast cancer.The FEBS journal · 2026Review
- Review
- Neuroinflammation after stroke: initiation, amplification and therapeutic prospects.Journal of translational medicine · 2026Review
- Matrix Metalloproteinase Inhibition in Melanoma.Experimental dermatology · 2026Review
- MMP-9 regulates disulphide isomerase activity of TGM2 to enhance fusion glycoprotein-mediated syncytium formation of respiratory syncytial virus.Protein & cell · 2026Article
- A Narrative Review of Salivary Gland Extracellular Matrix and Sjögren's Syndrome: Research Status and Future Prospects.Biomolecules · 2026Review
- Identification and validation of biomarkers associated with cellular senescence and demethylation in acute myocardial infarction.Scientific reports · 2025Article
- Targeting neutrophils for cancer therapy.Nature reviews. Drug discovery · 2025Review
- Inhibition of Metalloproteinases-2, -9, and -14 Suppresses Papillary Thyroid Carcinoma Cell Migration and Invasion.International journal of molecular sciences · 2025Article
- Matrix Metalloproteinases and Their Inhibitors in the Pathogenesis of Epithelial Differentiation, Vascular Disease, Endometriosis, and Ocular Fibrotic Pterygium.International journal of molecular sciences · 2025Review
- Enhancing adhesive performance with N, N, N', N'-tetrakis (2-pyridyl methyl) ethylenediamine matrix metalloproteinase inhibitors: A comprehensive study of degree of conversion, microleakage, and micro-tensile bond strength in dental adhesives.Journal of conservative dentistry and endodontics · 2025Article
- Matrix Metalloproteinase-9 is associated with tumor microenvironment remodeling of bladder cancer.Biology direct · 2025Article
- Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2024Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 of this therapeutic approach. 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.