Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases
| Autor: | Cho Tang, Flora Tang, Gerald McMahon, Ngoc Tran, Peter Hirth, Li Sun, Harald App |
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| Rok vydání: | 1998 |
| Předmět: |
Indoles
Magnetic Resonance Spectroscopy Stereochemistry Receptor ErbB-2 Receptor tyrosine kinase Receptor IGF Type 1 Structure-Activity Relationship Drug Discovery Structure–activity relationship Humans Receptors Growth Factor Receptors Platelet-Derived Growth Factor Enzyme Inhibitors Phosphorylation Cells Cultured chemistry.chemical_classification biology Chemistry Autophosphorylation Receptor Protein-Tyrosine Kinases Stereoisomerism Protein-Tyrosine Kinases ErbB Receptors Receptors Vascular Endothelial Growth Factor Biochemistry Heterocyclic compound biology.protein Molecular Medicine Signal transduction Tyrosine kinase Platelet-derived growth factor receptor |
| Zdroj: | Journal of medicinal chemistry. 41(14) |
| ISSN: | 0022-2623 |
| Popis: | 3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs). These compounds have been evaluated for their relative inhibitory properties against a panel of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified compounds which showed selective inhibition of the ligand-dependent autophosphorylation of various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds and their relative potency and selectivity to inhibit particular RTKs has determined that (1) 3-[(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C-3 position of the indolin-2-one (16) exhibited high potency and selectivity when tested against the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these 3-substituted indolin-2-ones provides a rationale to suggest that these compounds may bind in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets of these compounds as specific chemical leads for the development of RTK-specific drugs with broad application for the treatment of human diseases. |
| Databáze: | OpenAIRE |
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