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Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit
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2003 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 9, 2007-2018 p.Article in journal (Refereed) Published
Abstract [en]

Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is approximately 15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.

Place, publisher, year, edition, pages
2003. Vol. 11, no 9, 2007-2018 p.
Keyword [en]
Animals, Cell Line, Enzyme Inhibitors/chemistry/*pharmacology, Humans, Proto-Oncogene Proteins/*antagonists & inhibitors/metabolism, Proto-Oncogene Proteins c-kit/*metabolism, Quinoxalines/chemistry/*pharmacology, Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism, Receptors; Platelet-Derived Growth Factor/*antagonists & inhibitors/metabolism, Swine, fms-Like Tyrosine Kinase 3
National Category
Medical and Health Sciences Natural Sciences
URN: urn:nbn:se:uu:diva-10494DOI: 10.1016/S0968-0896(03)00048-8PubMedID: 12670652OAI: oai:DiVA.org:uu-10494DiVA: diva2:38262
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2013-10-30Bibliographically approved

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Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12670652&dopt=Citation

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Sjöblom, Tobias
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