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.

摘要: 3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor kinases (RTKs). These compounds evaluated for their relative inhibitory properties against panel RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we identified showed selective inhibition ligand-dependent autophosphorylation various at submicromolar levels Structure-activity analysis these potency to inhibit particular has determined that (1) 3-[(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) phenyl ring C-3 position high EGF Her-2 RTKs, (3) compound an extended side chain indolin-2-one (16) exhibited when tested PDGF RTKs. Recent published crystallographic data two provides rationale suggest may bind ATP binding pocket The structure-activity supports use subsets chemical leads development RTK-specific drugs with broad application treatment human diseases.