Novel Bis(1H-indol-2-yl)methanones as Potent Inhibitors of FLT3 and Platelet-Derived Growth Factor Receptor Tyrosine Kinase
| Autor: | Stefan Dove, Christophe Cénac, Siavosh Mahboobi, Harald Hufsky, Florian H. Heidel, Thomas Fischer, Andreas Sellmer, Emerich Eichhorn, Herwig Pongratz, Andrea Uecker, Frank-D. Böhmer, Heymo Höcher, Sigurd Elz, Antje Trümpler, Marit Sicker, Carol Stocking |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Indoles Antineoplastic Agents Apoptosis In Vitro Techniques Ligands Receptor tyrosine kinase Cell Line Mice Structure-Activity Relationship fluids and secretions Growth factor receptor Cell Line Tumor hemic and lymphatic diseases Drug Discovery Animals Humans Pyrroles Receptors Platelet-Derived Growth Factor Phosphorylation Binding Sites biology Kinase Chemistry Autophosphorylation hemic and immune systems fms-Like Tyrosine Kinase 3 Biochemistry Leukemia Myeloid Enzyme inhibitor Acute Disease embryonic structures biology.protein Molecular Medicine Signal transduction Tyrosine kinase Platelet-derived growth factor receptor |
| Zdroj: | Journal of Medicinal Chemistry. 49:3101-3115 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm058033i |
| Popis: | FLT3 receptor tyrosine kinase is aberrantly active in many cases of acute myeloid leukemia (AML). Recently, bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. To optimize FLT3 activity and selectivity, 35 novel derivatives were synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. The most potent FLT3 inhibitors 98 and 102 show IC50 values of 0.06 and 0.04 microM, respectively, and 1 order of magnitude lower PDGFR inhibiting activity. The derivatives 76 and 82 are 20- to 40-fold PDGFR selective. Docking at the recent FLT3 structure suggests a bidentate binding mode with the backbone of Cys-694. Activity and selectivity can be related to interactions of one indole moiety with a hydrophobic pocket including Phe-691, the only different binding site residue (PDGFR Thr-681). Compound 102 inhibited the proliferation of 32D cells expressing wildtype FLT3 or FLT3-ITD similarly as FLT3 autophosphorylation, and induced apoptosis in primary AML patient blasts. |
| Databáze: | OpenAIRE |
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