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-Rβ Tyrosine Kinases

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.

Novel targeted therapeutics for MEN2

“…Sunitinib was part of a large indolinone compound collection at SUGEN Inc (later acquired by Pfizer), which was initially developed to block angiogenic kinases belonging to the split tyrosine kinase domain family (VEGFR, FGFR, PDGFR) (Sun et al 1998(Sun et al , 1999(Sun et al , 2000. Later, a few closely related compounds from this series were shown to inhibit RET at submicromolar concentrations in vitro and in vivo (Kim et al 2006, Mologni et al 2006, Chow & Eckhardt 2007, Jeong et al 2011.…”

VEGF121 and VEGF165 Regulate Blood Vessel Diameter Through Vascular Endothelial Growth Factor Receptor 2 in an in vitro Angiogenesis Model

“…To determine whether VEGFR-2 is necessary for sprouting and vessel development in this system, we used a well-characterized inhibitor that competes with ATP in the active site of VEGFR-2 (Sun et al, 2000). We performed a doseresponse experiment using a range of concentrations from 0.001 M to 1 M and quantified sprouting and vessel growth.…”

Vascular endothelial growth factor and its receptors in multiple myeloma

“…Small selective nonimmunogenic synthetic molecules have shown specific activity associated with an acceptable toxicity profile and good resistance to enzyme lysis. 81 These compounds show good inhibition of VEGFR and may inhibit tumor cells expressing these targets. Inhibition of VEGFR signaling pathway can downregulate angiogenesis and its associated features in bone marrow of patients with MM.…”