FIGURE 9.10 Events triggered after activation of VEGFR-1 and VEGFR-2.

VEGFR-1 was the first receptor TK to be identified and its signalling can be important in tumor growth and metastasis, including the induction of matrix metalloproteinases (MMPs). VEGFR-2 is expressed in endothelial cells and is the principal receptor through which VEGFs exert their mitogenic, chemotactic, and vascular permeabilizing effects on the host vasculature (Fig. 9.10). Activation of VEGFR-3 promotes lymphangiogenesis.

3.4.1. VEGFR inhibitors

Indolinone derivatives have in common the presence of a hydrogen bond between the C-2 carbonyl and a hydrogen donor in a side chain, generally a pyrrole ring. The first of them was semaxanib (SU-5416), identified in a high-throughput library screening as an inhibitor of VEGF- and PDGF-induced tyrosine autopho-sphorylation. This compound reached Phase III clinical trials for colorectal cancer, but it was discontinued at that stage.21 SU-666822 and sunitinib (SU-11248)

23 , were obtained by introduction of a propionic acid and a (diethylaminoethyl)carmaboyl chain, respectively, at the C-4' position of the latter compound. Sunitinib has been approved by the FDA for gastrointestinal and renal cancer.


Semaxanib (SU-5416)

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