Related Experiment Video
Updated: Jun 25, 2026
A Flow Cytometry-Based High-Throughput Technique for Screening Integrin-Inhibitory Drugs
Published on: February 2, 2024
Computer aided identification of small molecules disrupting uPAR/alpha5beta1--integrin interaction: a new paradigm
Pratima Chaurasia1, Mihaly Mezei, Ming-Ming Zhou
1Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Background:
Disseminated dormant cancer cells can resume growth and eventually form overt metastases, but the underlying molecular mechanism responsible for this change remains obscure. We previously established that cell surface interaction between urokinase receptor (uPAR) and alpha5beta1-integrin initiates a sequel of events, involving MAPK-ERK activation that culminates in progressive cancer growth. We also identified the site on uPAR that binds alpha5beta1-integrin. Disruption of uPAR/integrin interaction blocks ERK activation and forces cancer cells into dormancy.
Methods And Principle Findings:
Using a target structure guided computation docking we identified 68 compounds from a diversity library of 13,000 small molecules that were predicted to interact with a previously identified integrin-binding site on uPAR. Of these 68 chemical hits, ten inhibited ERK activation in a cellular assay and of those, 2 compounds, 2-(Pyridin-2-ylamino)-quinolin-8-ol and, 2,2'-(methylimino)di (8-quinolinol) inhibited ERK activation by disrupting the uPAR/integrins interaction. These two compounds, when applied in vivo, inhibited ERK activity and tumor growth and blocked metastases of a model head and neck carcinoma.
Conclusions/Significance:
We showed that interaction between two large proteins (uPAR and alpha5beta1-integrin) can be disrupted by a small molecule leading to profound downstream effects. Because this interaction occurs in cells with high uPAR expression, a property almost exclusive to cancer cells, we expect a new therapy based on these lead compounds to be cancer cell specific and minimally toxic. This treatment, rather than killing disseminated metastatic cells, should induce a protracted state of dormancy and prevent overt metastases.
Insights
Small molecules can disrupt cancer cell growth by blocking the urokinase receptor (uPAR) and alpha5beta1-integrin interaction, preventing metastasis. This targeted approach inhibits ERK activation, inducing dormancy and minimizing toxicity for a novel cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Disseminated dormant cancer cells pose a threat for metastasis, but the mechanisms driving their reactivation are unclear.
- Urokinase receptor (uPAR) and alpha5beta1-integrin interaction activates MAPK-ERK signaling, promoting cancer growth.
- Disrupting this uPAR/integrin interaction induces cancer cell dormancy.
Purpose of the Study:
- To identify small molecules that disrupt the uPAR/integrin interaction.
- To evaluate the efficacy of these compounds in inhibiting cancer growth and metastasis.
Main Methods:
- Structure-guided computational docking identified potential small molecule inhibitors.
- Cellular assays assessed ERK activation inhibition.
- In vivo studies evaluated tumor growth and metastasis in a head and neck carcinoma model.
Main Results:
- 68 compounds were predicted to interact with the uPAR integrin-binding site.
- Two compounds, 2-(Pyridin-2-ylamino)-quinolin-8-ol and 2,2'-(methylimino)di (8-quinolinol), inhibited ERK activation by disrupting uPAR/integrin interaction.
- In vivo, these compounds inhibited ERK activity, tumor growth, and metastasis.
Conclusions:
- Small molecules can effectively disrupt protein-protein interactions like uPAR/integrin.
- This disruption leads to profound downstream effects, including cancer cell dormancy.
- Lead compounds offer potential for cancer-specific therapies with minimal toxicity, aiming to induce dormancy rather than cell death.
Related Concept Videos
01:15Activation of Integrins
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
01:17Intracellular Signaling Affects Focal Adhesions
Some...
01:10Integrins
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...