Malignant glioma is the most commonly diagnosed primary brain cancer. Despite advances in diagnosis and therapy, these tumors show a high incidence of recurrence, have a poor prognosis and lack effective therapies. Recent advances in tumor molecular biology have led to renewed interest and heightened optimism for the development of new therapeutics for the treatment of human glioma. Receptor tyrosine kinases have become major targets for cancer therapy due to their critical roles in tumor growth, invasion, metastasis and angiogenesis. c-Met, the receptor tyrosine kinase for scatter factor/hepatocyte growth factor (SF/HGF) has been shown to be over-expressed or mutated in a variety of solid tumors including gliomas. Binding of SF/HGF to its receptor promotes growth of both tumor cells and endothelial cells lining the tumor's blood supply. Antagonism of the c-Met-SF/HGF pathway is thus an attractive multi-faceted approach to targeting the tumor cell that also may reduce the risk of therapy-induced resistance by blocking multiple events involved in disease progression. In previous work we identified a new class of c-Met antagonists (with lead compound ANG 797) that compete at the ATP-binding site of c-Met, block c-Met activation and inhibit down-stream signaling events initiated by SF/HGF. We found that ANG 797 also targets another receptor tyrosine kinase, Tie-2, involved in angiogenesis and in particular with sustaining tumor neovascularization. In vivo ANG 797 attenuates tumor growth and improves survival in orthotopic models of human glioma. Recent data have demonstrated that the activity and selectivity of ANG 797 can be improved by modifying substituents on its 2,4-diaminoquinazoline scaffold. In particular, ANG 1490, a newly prepared ANG 797 analog with a different substituent at the 4 position, shows 12-fold greater inhibitory activity and increased specificity to the HGF/SF/c-Met pathway, with better water solubility than ANG 797. In a preliminary in vivo lung tumor study it showed anti-tumor activity with a trend toward improved, but not statistically significant, activity over ANG 797. This Phase I application is focused on further optimization of the 2,4-diaminoquinazoline scaffold with the goal of identifying more potent c-Met/Tie-2 antagonists that can be advanced towards clinical development. Additional synthetic work based on the recent significant improvement in activity, in combination with assessment of inhibitory activity of new analogs towards in vitro cellular and kinase targets and in an in vivo tumor model, will be focused on identifying an optimized lead for entry into preclinical development in a future SBIR Phase 2 application. ? ? ?
