Mahboobi, Siavosh and Teller, S. and Pongratz, H. and Hufsky, H. and Sellmer, A. and Botzki, Alexander and Uecker, A. and Beckers, T. and Baasner, S. and Schächtele, C. and Überall, F. and Kassack, M. U. and Dove, Stefan and Böhmer, F.-D. (2002) Bis(1H-2-indolyl)methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase. Journal of Medicinal Chemistry 45 (5), pp. 1002-1018.
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The novel lead bis(1H-2-indolyl)methanone inhibits autophosphorylation of platelet-derived growth factor (PDGF) receptor tyrosine kinase in intact cells. Various substituents in the 5- or 6-position of one indole ring increase or preserve potency, whereas most modifications of the ring structures and of the methanone group as well as substitution at both indoles result in weak or no activity. An ATP binding site model, derived by homol. from the FGFR-1 tyrosine kinase crystal structure suggesting hydrogen bonds of one indole NH and the methanone oxygen with the backbone carbonyl and amide, resp., of Cys684, explains why only one indole moiety is open for substitution and locates groups in the 5- or 6-position outside the pocket. Some of the most active derivs., inhibit both isoforms of the PDGF receptor kinase in intact cells, with IC50 of 0.1-0.3 mM, and purified PDGFb-receptor in vitro, with IC50 of 0.09, 0.1, or 0.02 mM, resp. PDGF-stimulated DNA synthesis is inhibited by these derivs. with IC50 values of 1-3 mM. Kinetic anal. of one compd. showed an ATP-competitive mode of inhibition. The compds. are inactive or weakly active toward a no. of other tyrosine kinases, including the FGF receptor 1, EGF receptor, and c-Src kinase, as well as toward serine-threonine kinases, including different PKC isoforms and GRK2, and appear therefore selective for PDGF receptor inhibition.
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz)
|Projects:||Deutsche Krebshilfe 10-2100|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
600 Technology > 610 Medical sciences Medicine
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Partially|
|Owner:||Prof. Dr. Stefan Dove|
|Deposited On:||20 Jan 2009 16:41|
|Last Modified:||05 Aug 2009 13:50|