Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors

Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (<b>1</b>–<b>3</b>) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound <b>2</b> were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. Although compounds <b>1</b>–<b>3</b> acted as dual inhibitors, the heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. Furthermore, molecular modeling studies allowed the rationalization of the pharmacodynamic properties of the compounds