title: Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Pace
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Albert M
authors.initials: AM
authors.lastname: DeBerardinis
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Vibhavari
authors.initials: V
authors.lastname: Sail
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute , 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, United States.
authors.forename: Silvia K
authors.initials: SK
authors.lastname: Tacheva-Grigorova
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Chan
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Tran
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Raccuia
authors.affiliation: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute , 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002460:Cell Line; D020128:Inhibitory Concentration 50; D017964:Itraconazole / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; C498520:Gli1 protein, mouse; D012333:RNA, Messenger; D000071676:Zinc Finger Protein GLI1; D017964:Itraconazole