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Contextual compound screening for improved therapeutic discovery

Evensen, L and Odlo, K and Micklem, DR and Littlewood-Evans, A and Wood, J and Kuzniewski, C and Altmann, K and Hansen, TV and Lorens, JB (2013) Contextual compound screening for improved therapeutic discovery. ChemBioChem. pp. 2512-2518.

Abstract

Cellular behaviors are governed by combinations of systemic and microenvironmental factors; together, these regulate cell signaling responses to growth factors. This contextual microenvironmental influence also determines drug sensitivity. Hence using in vitro systems that model contextual cellular behavior is highly beneficial for effective therapeutic development. Angiogenesis (formation of blood vessels) is driven by a series of dynamic endothelial cell signaling responses to growth factors under the influence of the vascular extracellular matrix and adjacent pericytes. In vitro primary human vascular cell co-cultures self-assemble into capillary-like structures through reciprocal heterotypic interactions that mimic angiogenic context dynamics. By using temporal live-cell imaging-based analysis, unique angiogenic microenvironments can be delineated to quantify the contextual activity of compound inhibitors. We used this in vitro organotypic contextual screening approach to conduct structure-activity relationship analysis on a combretastatin A-4 analogue series to identify novel compounds with potent vascular disrupting activity in vivo. Context is everything: Microenvironmental factors that regulate cellular responses influence drug sensitivity. Organotypic model systems combined with temporal live-cell imaging can detect and quantify cellular dynamics; this can be used to quantify the contextual activity of compound inhibitors and identify novel compounds with potent activity in vivo. Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Item Type: Article
Additional Information: pubid: 55 nvp_institute: NIBR contributor_address: (Evensen, Micklem, Lorens) Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway (Odlo, Hansen) Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Sem Saelands vei 3, 0371 Oslo, Norway (Littlewood-Evans, Wood) Oncology Research, Novartis Institutes for BioMedical Research, Klybeckstrasse, 4002 Basel, Switzerland (Kuzniewski, Altmann) Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093, Zurich, Switzerland
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21903

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