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-Rbeta tyrosine kinases.

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Sun L, Tran N, Liang C, Hubbard S, Tang F, Lipson K, Schreck R, Zhou Y, McMahon G, Tang C

J Med Chem. 2000 Jul 13;43(14):2655-63.

PubMed ID

10893303 [ View in PubMed

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Abstract

A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-Rbeta, p60(c)()(-)()(Src)(), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-Rbeta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-[(3-(2-CARBOXYETHYL)-4-METHYLPYRROL-2-YL)METHYLENE]-2-INDOLINONE	Fibroblast growth factor receptor 1	IC 50 (nM)	30	7.5	22	Details
Semaxanib	Vascular endothelial growth factor receptor 2	IC 50 (nM)	700	7.5	22	Details