Repurposing the Clinically Efficacious Anti-Fungal Agent Itraconazole as an Anti-Cancer Chemotherapeutic

Itraconazole (ITZ) is an FDA-approved member of the triazole class of anti-fungal agents. Two recent drug repurposing screens identified ITZ as a promising anti-cancer chemotherapeutic that inhibits both angiogenesis and the hedgehog (Hh) signaling pathway. We have synthesized and evaluated first and second generation ITZ analogues for their anti-Hh and anti-angiogenic activities to more fully probe the structural requirements for these anti-cancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis, but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des -triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anti-cancer properties of the ITZ scaffold.