In a screen of the Johns Hopkins Drug Library for inhibitors of endothelial cell proliferation, an antifungal drug, itraconazole, was identified as a novel inhibitor of angiogenesis. Earlier studies revealed several important cellular activities of itraconazole underlying its anti-angiogenic effect, including inhibition of endothelial cell cycle t G1 and mTOR signaling pathway. Itraconazole also showed remarkable anti-angiogenic activity in vitro and in various animal models of angiogenesis and tumor xenografts in vivo. Moreover, itraconazole has entered multiple Phase 2 human clinical studies as a new treatment of lung, prostate and skin cancer and how shown significant efficacy. Using a clickable photoaffinity probe of itraconazole, a major binding protein of itraconazole has been identified. Preliminary studies showed that knocking down of newly identified itraconazle-binding protein led to the inhibition of mTOR in endothelial cells. Furthermore, a signaling kinase downstream of the itraconazole-binding protein that is known to be a negative regulator of mTOR was also found to be activated by itraconazole. This application will be focused on the characterization and validation of the newly identified itraconazole-binding protein as a direct target and its downstream kinase as key mediator of the antiangiogenic activity of itraconazole. Attempts will also be made to obtain a crystal structure of the complex between itracoanzole and its putative target. New analogs of itraconazole will be synthesized by systematically altering the different structural domains of itraconazole to improve its anti-angiogenic potency, its solubility while decreasing its inhibition of CYP3A3 drug-metabolizing enzyme and its hepatotoxicity. It is hoped that the successful completion of the project will facilitate the clinical development of itraconazole and analogs as the next generation of a new mechanistic class of angiogenesis drugs.
New use of old drugs can significantly accelerate the translation of discoveries at the bench to treatments in the clinic. The application is aimed at investigating the molecular basis of the newly discovered anti-angiogenic activity of an existing antifungal drug itraconazole, and synthesizing new analogs of itraconazole in attempts to improve its potency and decreased its side effects.
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|Head, Sarah A; Shi, Wei; Zhao, Liang et al. (2015) Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci U S A 112:E7276-85|