Tumor-induced neovascularization and loss of cell cycle control are major drivers of human tumor growth. The endothelial cell specific vascular endothelial growth factor (VEGF) / VEGF-receptor tyrosine kinase (VEGF-RTK) system has recently been clinically validated as a key signaling pathway in tumor angiogenesis. Besides having direct impact on tumor cell proliferation, the related platelet-derived growth factor (PDGF) / PDGF-RTK system stimulates lymphangiogenesis, plays an important role in pericyte endothelial cell interaction and contributes to tumor angiogenesis. The cyclin-dependent kinase (CDK) - Retinoblastoma - E2F pathway was found to be deregulated by various mutations and/or altered expression profiles in human cancers. ZK-304709, the Multi-target Tumor Growth Inhibitor™, is a pyrimidine based nanomolar inhibitor of CDKs1, 2, 4 & 7, VEGF-RTKs1-3 and PDGF-RTKβ, undergoing phase I clinical trials. The compound potently inhibits proliferation of various human tumor cells in the nanomolar range. Flow cytometric assays indicate that the compound blocks cell cycle progression consistent with CDK inhibition. Western blot analysis of tumor cell lysates showed that 1 micromolar of ZK-304709 was sufficient to inhibit phosphorylation of retinoblastoma protein in MCF7 cells. Inhibition of VEGF-induced vascular permeability, as measured by Evans blue dye extravasation (Miles assay) in nude mice, indicates that ZK-304709 blocks the VEGF-RTK system in vivo. Oral treatment of MaTu human estrogen-independent xenograft tumors of a volume of approx. 350 mm3 results in inhibition of phosphorylation of intratumoral retinoblastoma protein, induction of massive apoptosis, and regression of the tumors. These data clearly show that the compound is able to quantitatively inhibit the anticipated pathways in vivo. Furthermore, ZK-304709 is well tolerated by nude mice at therapeutic doses upon daily oral application for more than 70 days. The multi-target mechanism of action of ZK-304709 attacking tumor cells via inhibition of cell cycle progression and attacking tumor neovascularization via inhibition of VEGF- and PDGF-RTKs results in highly efficacious inhibition of growth of human tumor xenografts.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]