Axl tyrosine kinase is a putative driver of diverse cellular processes that are critical for the development, growth, and spread of tumors. It is a promising therapeutic target for cancer therapy. VEGFR2 is a primary responder to vascular endothelial growth factor signal, and thereby regulates endothelial migration and proliferation. High throughput screening identified a dual Axl/VEGF-R2 inhibitor, R916562. The IC50s are 36 and 24 nM, respectively.

In addition, R916562 exhibits anti-tumor activity in human breast cancer xenograft model. The treatment at 85 mg/kg orally b.i.d for 21 days results in statistically significant tumor growth inhibition (TGI) of 69%. The TGI is 83% at 125 mg/kg orally b.i. d for 21 days. Comparably, the positive control Sunitinib, results in 84% TGI given once daily at 80 mg/kg.

Moreover, R916562 is effective in the Caki-1 human renal carcinoma xenograft model. The TGI was 80% using 85 mg/kg b.i.d R916562, comparable to 85% TGI with Sunitinib (80 mg/kg, once daily) in this model.

Finally, in a mouse corneal micropocket, R916562 showed 73% reduction in fibroblast growth factor–induced neovascularization at a dose of 100 mg/kg. The anti-angiogenic effect was also comparable to that of the positive control Sunitinib (78% reduction at 80 mg/kg).

To conclude, R916562 could be a potential anti-angiogenic and anti-metastatic drug for cancer chemotherapy. By targeting multiple biological pathways involved with angiogenesis and tumorogenesis, the dual Axl/VEGF inhibitors might be very effective oncology therapeutics.