Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic

Abstract

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.

Structure–Activity Relationship Studies of Vitamin D3 Analogues Containing an Ether or Thioether Linker as Hedgehog Pathway Inhibitors

“…Interestingly, the anilines were all more potent in ASZ001 cells (IC 50 values 0.5–0.9 μ m ) when compared with the mouse embryonic fibroblasts (MEFs). Of note, analogues of itraconazole have demonstrated the same trend in our hands, but previous series of VD3 analogues have maintained similar inhibition between the two distinct cell types . The most potent analogue in this series was 17 , which contains the 3a R ,4 R hexahydroindane scaffold (IC 50 =0.5 μ m ).…”

The antifungal pipeline: a reality check

“…On a similar note, a new oral preparation of itraconazole (also known as ‘super bioavailability’ (SUBA)-itraconazole ; Mayne Pharma) is under investigation for the treatment of patients with basal cell carcinoma nevus syndrome (NCT02354261). The anticancer properties of itraconazole come from its inhibition of both angiogenesis and Hedgehog signalling 124 . However, the new nanosuspension formulation has improved bioavailability 125 , so it might be co-opted again by clinicians for its antifungal activity, and Mayne Pharma could direct efforts towards its development in the antifungal arena.…”

Co-delivery of doxorubicin and itraconazole by Pluronic® P123 coated liposomes to enhance the anticancer effect in breast cancers

“…The tumor grew rapidly in saline treated animals. In contrast, ITZ showed weak antitumor efficiency with TGI of 30.39% probably due to its antiangiogenesis effect on tumor, 38 which was consistent with the results of in vitro cytotoxicity experiments. Mice treated with DOX exhibited modest inhibitory effect on tumor growth with TGI of 57.65%.…”