Computer aided identification of small molecules disrupting uPAR/alpha5beta1--integrin interaction: a new paradigm for metastasis prevention.
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.


RESULTS
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
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.
Chaurasia
Pratima
P
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Mezei
Mihaly
M
Zhou
Ming-Ming
MM
Ossowski
Liliana
L
D000970:Antineoplastic Agents; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008958:Models, Molecular; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009930:Organic Chemicals / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D054852:Small Molecule Libraries
D000970:Antineoplastic Agents; D039081:Integrin alpha5beta1; D009930:Organic Chemicals; D055293:Receptors, Urokinase Plasminogen Activator; D054852:Small Molecule Libraries