Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
| Autor: | Daniel S. Raccuia, Robert J. Wechsler-Reya, Albert M. DeBerardinis, Silvia K. Tacheva-Grigorova, Vibhavari Sail, Kelly A. Chan, Raymond Tran, M. Kyle Hadden, Jennifer R Pace |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Antifungal Hh signaling Antifungal Agents Angiogenesis medicine.drug_class Itraconazole Triazole Antineoplastic Agents Pharmacology Zinc Finger Protein GLI1 Article Cell Line 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 Mice 0302 clinical medicine Drug Discovery medicine Inhibitory concentration 50 Animals RNA Messenger Repurposing Mice Inbred C3H Drug repositioning 030104 developmental biology chemistry 030220 oncology & carcinogenesis Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 59(8) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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