Identification of substituted 3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-R beta tyrosine kinases

A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases as sociated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These comp ounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/ KDR), FGF-R1, PDGF-R beta, p60(c-Src), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-a ctivity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety a t the C-3' position of the tetrahydroindole ring represented the most poten t indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. Th e inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, a nd 9b against PDGF-R beta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kin ase. Compounds 9a and 9b represented the most potent inhibitors of these cl asses to inhibit both biochemical kinase and growth factor-dependent cell p roliferation for these three targets. In addition, compound 9a was cocrysta llized with the catalytic domain of FGF-R1 providing evidence to explain th e structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the t reatment of angiogenesis and other growth factor-related diseases including human cancers.