title: Bis(1H-2-indolyl)methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase.
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 homology 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, respectively, of Cys684, explains why only one indole moiety is open for substitution and locates groups in the 5- or 6-position outside the pocket. The hitherto most active derivatives, 39, 53 and 67, inhibit both isoforms of the PDGF receptor kinase in intact cells, with IC(50) of 0.1-0.3 microM, and purified PDGFbeta-receptor in vitro, with IC(50) of 0.09, 0.1, or 0.02 microM, respectively. PDGF-stimulated DNA synthesis is inhibited by these derivatives with IC(50) values of 1-3 microM. Kinetic analysis of 53 showed an ATP-competitive mode of inhibition. The compounds are inactive or weakly active toward a number 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.
authors.affiliation: Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de
authors.forename: Siavosh
authors.initials: S
authors.lastname: Mahboobi
authors.forename: Steffen
authors.initials: S
authors.lastname: Teller
authors.forename: Herwig
authors.initials: H
authors.lastname: Pongratz
authors.forename: Harald
authors.initials: H
authors.lastname: Hufsky
authors.forename: Andreas
authors.initials: A
authors.lastname: Sellmer
authors.forename: Alexander
authors.initials: A
authors.lastname: Botzki
authors.forename: Andrea
authors.initials: A
authors.lastname: Uecker
authors.forename: Thomas
authors.initials: T
authors.lastname: Beckers
authors.forename: Silke
authors.initials: S
authors.lastname: Baasner
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Florian
authors.initials: F
authors.lastname: Uberall
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
authors.forename: Frank-D
authors.initials: FD
authors.lastname: Böhmer
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C450153:(2-(1H-2-indolylcarbonyl)-1H-5-indolyl) dimethylaminoethanoate; D004791:Enzyme Inhibitors; D007211:Indoles; D007659:Ketones; D017468:Receptors, Fibroblast Growth Factor; D004247:DNA; C496348:FGFR1 protein, human; C099852:PDGF receptor tyrosine kinase; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017479:Receptors, Platelet-Derived Growth Factor; D005998:Glycine