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- an...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-04, Vol.59 (8), p.3635-3649
Main Authors: Pace, Jennifer R, DeBerardinis, Albert M, Sail, Vibhavari, Tacheva-Grigorova, Silvia K, Chan, Kelly A, Tran, Raymond, Raccuia, Daniel S, Wechsler-Reya, Robert J, Hadden, M. Kyle
Format: Article
Language:English
Subjects:
Animals
Antifungal Agents - therapeutic use
Antineoplastic Agents - therapeutic use
Cell Line
Inhibitory Concentration 50
Itraconazole - therapeutic use
Mice
Mice, Inbred C3H
RNA, Messenger - genetics
Zinc Finger Protein GLI1 - genetics
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01718