Targeting Angiogenesis and Tumor Growth: The Therapeutic Efficacy of YL529 in Preclinical Cancer Models

The development of YL529, a small molecule inhibitor, is detailed in this study. It was created using computer-assisted drug design and was synthesized and screened for its potential in cancer therapy. The compound's biochemical, pharmacological, and toxicological properties were evaluated through various assays and models, including kinase and cell viability tests, a mouse model with tumor cells in alginate beads, a zebrafish angiogenesis model, and several xenograft models in mice.

In vitro studies demonstrated that YL529 selectively suppressed the activity of VEGFR2/VEGFR3 and RAF kinase, hindering VEGF165-induced VEGFR2 phosphorylation and the proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells. It also significantly reduced vascular formation and angiogenesis in the zebrafish model. Furthermore, YL529 strongly reduced the proliferation of A549 cells by disrupting the RAF/MAP/ERK kinase pathway.

Oral administration of YL529 to mice with established tumor xenografts resulted in a significant reduction in tumor growth, with no detectable toxicity. YL529 also decreased microvessel density and increased tumor cell apoptosis in the tumors formed by lung cancer cells and colon carcinoma cells.

The study concludes that YL529, an orally active multikinase inhibitor, has therapeutic potential for solid tumors and should be further explored as a potential anticancer agent.