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Design and profile of low-molecular-weight receptor tyrosine kinase inhibitors for antiangiogenic therapy

Angiogenesis occurs physiologically during embryogenesis, ovulation and wound healing, and pathologically in inflammation, psoriasis and tumor growth. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations that involve neovascularization as well as enhanced vascular permeability. Our aim was to design synthetic low-molecular-weight molecules that, by blocking the VEGF/VEGF receptor system after oral administration, can be used therapeutically. One compound we developed is PTK787/ZK 222584, a potent inhibitor of VEGF receptor tyrosine kinases that is active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-β tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2, or intracellular kinases such as c-Src, c-Abl, PKC-α. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell-based assays. In concentrations up to 1 μmol/l, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 μmol/l for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dose (25-100 mg/kg). In the same dose range, it also inhibits the growth of xenografted human carcinomas either solid or in ascites formation, as well as a murine renal carcinoma and its metastasis in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing or hematopoietic recovery after concomitant cytotoxic anticancer agent challenge.

Compounds that inhibit VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors, and may provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.

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Wood, J. Design and profile of low-molecular-weight receptor tyrosine kinase inhibitors for antiangiogenic therapy. Breast Cancer Res 3 (Suppl 1), A73 (2001).

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