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Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis

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† Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
‡ SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
§ Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States
∥ Faculty of Health Sciences, University of Macau, Taipa, Macau SAR China
⊥ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
# Division of Structural Biology & Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore
∇ Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
*Tel.: +1-410-955-4619. E-mail: [email protected]
Cite this: ACS Chem. Biol. 2017, 12, 1, 174–182
Publication Date (Web):November 22, 2016
https://doi.org/10.1021/acschembio.6b00849
Copyright © 2016 American Chemical Society
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    Abstract

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    The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis.

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