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

ABSTRACT: 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.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.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.

SUBMITTER: Chaurasia P

PROVIDER: S-EPMC2643475 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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

Chaurasia Pratima P Mezei Mihaly M Zhou Ming-Ming MM Ossowski Liliana L

PloS one 20090226 2

<h4>Background</h4>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 uPA ...[more]

PMID: 19242538

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Project description:Recent data indicates limited awareness and compliance on infection prevention procedures by dental offices and by dental laboratories. Guidelines for infection prevention in dentistry have been published by Centres for Disease Control and Prevention since 2003; the section "IX-Special consideration" includes a subsection concerning the prevention in dental laboratories, but it has not been modernised in later versions to fit the needs of traditional and computer-aided technology. Traditional techniques required disinfecting items (impression, chewing waxes, and appliances) with well-suited products, which are also chosen for limiting impression changes or appliance deterioration. Effective procedures are available with difficulties. Some of these contain irritant or non-eco-friendly disinfectants. The transport of impression, to dental laboratories, is often delayed with limited precautions for limiting cross-infection. Gypsum casts are frequently contaminated mainly by bacteria and their antibiotic-resistant strains and even stored for long periods during dental implant supported restoration and orthodontic therapy, becoming a hidden source of infection. Nowadays, computer-aided design/computer-aided manufacturing technology seems to be an interesting way to promote both business and safety, being more comfortable for patients and more accurate than traditional technology. A further advantage is easier infection prevention since, for the most part, mainly digital impression and casts are not a source of cross-infection and the transport of contaminated items is reduced and limited to try-in stages. Nevertheless, a peculiar feature is that a digital electronic file is of course unalterable, but may be ruined by a computer virus. Additionally, the reconditioning of scanner tips is determinant for the optical characteristics and long term use of the scanner, but information for its reconditioning from producers is often limited. This study focuses on some critical points including (a) insufficient guidelines, (b) choice of proper procedure for scanner reconditioning, and (c) data protection in relation to patient privacy.

Dataset Information

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

Publications

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

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