Mahboobi, Siavosh and Teller, Steffen and Pongratz, Herwig and Hufsky, Harald and Sellmer, Andreas and Botzki, Alexander and Uecker, Andrea and Beckers, Thomas and Baasner, Silke and Schaechtele, Christoph and Ueberall, Florian and Kassack, Matthias U. and Dove, Stefan and Boehmer, Frank-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. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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 IC50 of 0.1-0.3 muM, and purified PDGFbeta-receptor in vitro, with IC50 of 0.09, 0.1, or 0.02 muM, respectively. PDGF-stimulated DNA synthesis is inhibited by these derivatives with IC50 values of 1-3 muM. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FACTOR-BETA-RECEPTOR; TYROSINE KINASE; SIGNAL-TRANSDUCTION; IN-VITRO; CELL-GROWTH; PDGF; DOMAIN; EXPRESSION; MECHANISM; FGF; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Nov 2021 07:33 |
| Last Modified: | 09 Nov 2021 07:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/40576 |
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