Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression Article Swipe
Vishnu C. Damalanka
,
Jorine Voss
,
Matthew Mahoney
,
Tina Primeau
,
Shunqiang Li
,
Lidija Klampfer
,
James W. Janetka
·
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.1c01671
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.1c01671
Hepatocyte growth factor (HGF), the ligand for the MET receptor tyrosine kinase, is a tumor-promoting factor that is abundant in the tumor microenvironment. Proteolytic activation of inactive pro-HGF by one or more of the serine endopeptidases matriptase, hepsin, and HGF activator is the rate-limiting step in HGF/MET signaling. Herein, we have rationally designed a novel class of side chain cyclized macrocyclic peptide inhibitors. The new series of cyclic tripeptides has superior metabolic stability and significantly improved pharmacokinetics in mice relative to the corresponding linear peptides. We identified the lead compound VD2173 that potently inhibits matriptase and hepsin, which was tested in parallel alongside the acyclic inhibitor ZFH7116 using both in vitro and in vivo models of lung cancer. We demonstrated that both compounds block pro-HGF activation, abrogate HGF-mediated wound healing, and overcome resistance to EGFR- and MET-targeted therapy in lung cancer models. Furthermore, VD2173 inhibited HGF-dependent growth of lung cancer tumors in mice.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1021/acs.jmedchem.1c01671
- OA Status
- green
- Cited By
- 12
- References
- 78
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4200494140
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4200494140Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1021/acs.jmedchem.1c01671Digital Object Identifier
- Title
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Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer ProgressionWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2021Year of publication
- Publication date
-
2021-12-13Full publication date if available
- Authors
-
Vishnu C. Damalanka, Jorine Voss, Matthew Mahoney, Tina Primeau, Shunqiang Li, Lidija Klampfer, James W. JanetkaList of authors in order
- Landing page
-
https://doi.org/10.1021/acs.jmedchem.1c01671Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.ncbi.nlm.nih.gov/pmc/articles/9307089Direct OA link when available
- Concepts
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Chemistry, Hepatocyte growth factor, Cancer research, Tyrosine kinase, Proteases, C-Met, Receptor tyrosine kinase, Serine, Biochemistry, Pharmacology, Kinase, Signal transduction, Receptor, Phosphorylation, Enzyme, BiologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
12Total citation count in OpenAlex
- Citations by year (recent)
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2025: 2, 2024: 5, 2023: 4, 2022: 1Per-year citation counts (last 5 years)
- References (count)
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78Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| corresponding_author_ids | https://openalex.org/A5049539326 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 7 |
| corresponding_institution_ids | https://openalex.org/I204465549 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.800000011920929 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.80875484 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |