Computer Aided Identification of Small Molecules Disrupting uPAR-α5β1- Integrin Interaction: A New Paradigm for Metastasis PreventionReportar como inadecuado




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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 α5β1-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 α5β1-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′-methyliminodi 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 α5β1-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.



Autor: Pratima Chaurasia, Mihaly Mezei, Ming-Ming Zhou, Liliana Ossowski

Fuente: http://plos.srce.hr/



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