{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T01:23:21Z","timestamp":1776648201203,"version":"3.51.2"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2011,12,6]],"date-time":"2011-12-06T00:00:00Z","timestamp":1323129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,1]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold>The potent pro\u2010angiogenic growth factors VEGF\u2010A and basic fibroblast growth factor (bFGF) exert their effects by binding VEGF receptor 2 and FGF receptor tyrosine kinases, respectively. Indolinones (e.g. SU5416 and Sutent) and anilinophthalazines (e.g. PTK787) are potent small molecule inhibitors of VEGFR2 and other tyrosine kinases, but their effects on VEGF\u2010A\u2010 and bFGF\u2010stimulated endothelial responses are unclear. Here we assess the ability of these compounds to inhibit pro\u2010angiogenic responses through perturbation of receptor activity and endothelial function(s).<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>We used<jats:italic>in silico<\/jats:italic>modelling,<jats:italic>in vitro<\/jats:italic>tyrosine kinase assays, biochemistry and microscopy to evaluate the effects of small molecules on receptor tyrosine kinase activation and intracellular signalling. Primary human endothelial cells were used to assess intracellular signalling, cell migration, proliferation and tubulogenesis.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>We predicted that the anilinophthalazine PTK787 binds the tyrosine kinase activation loop whereas indolinones are predicted to bind within the hinge region of the split kinase domain. Sutent is a potent inhibitor of both VEGFR2 and FGFR1 tyrosine kinase activity<jats:italic>in vitro<\/jats:italic>. The compounds inhibit both ligand\u2010dependent and \u2010independent VEGFR2 trafficking events, are not selective for endothelial cell responses and inhibit both VEGF\u2010A\u2010 and bFGF\u2010mediated migration, wound healing and tubulogenesis at low concentrations.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold>We propose that these compounds have novel properties including inhibition of bFGF\u2010mediated endothelial responses and perturbation of VEGFR2 trafficking. Differential inhibitor binding to receptor tyrosine kinases translates into more potent inhibition of bFGF\u2010 and VEGF\u2010A\u2010mediated intracellular signalling, cell migration and tubulogenesis. Indolinones and anilinophthalazines thus belong to a class of multi\u2010kinase inhibitors that show clinical efficacy in disease therapy.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2011.01545.x","type":"journal-article","created":{"date-parts":[[2011,6,23]],"date-time":"2011-06-23T12:39:49Z","timestamp":1308832789000},"page":"245-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Indolinones and anilinophthalazines differentially target VEGF\u2010A\u2010 and basic fibroblast growth factor\u2010mediated responses in primary human endothelial 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