Abstract
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. ...
Abstract
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.
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