Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

Itraconazole
(ITZ) is an FDA-approved member of the triazole class
of antifungal agents. Two recent drug repurposing screens identified
ITZ as a promising anticancer chemotherapeutic that inhibits both
the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized
and evaluated first- and second-generation ITZ analogues for their
anti-Hh and antiangiogenic activities to probe more fully the structural
requirements for these anticancer 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 anticancer
properties of the ITZ scaffold.