PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration

PTR787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succi nate) is a potent inhibitor of vascular endothelial growth factor (VEGF) re ceptor tyrosine kinases, active in the submicromolar range. It also inhibit s other class III kinases, such as the platelet-derived growth factor (PDGF ) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrat ions. It is not active against kinases from other receptor families, such a s epidermal growth factor receptor, fibroblast growth factor receptor-1, c- Met, and Tie-2, or intracellular kinases such as C-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell prolife ration, migration, and survival in the nanomolar range in cell-based assays . In concentrations up to 1 mu M, PTK787/ZK 222584 does not have any cytoto xic 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 mu M for more than 8 h. PTK787/ZK 222584 induces dose -dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth fac tor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhi bits the growth of several human carcinomas, grown s.c. in nude mice, as we d as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvess el formation in the interior of the tumor. PTK787/ZK 222584 is very well to lerated and does not impair wound healing. It also does not have any signif icant effects on circulating blood cells or bone marrow leukocytes as a sin gle agent or impair hematopoetic recovery after concomitant cytotoxic anti- cancer agent challenge. This novel compound has therapeutic potential for t he treatment of solid tumors and other diseases where angiogenesis plays an important role.