Abstract 3666: Synthesis and evaluation of itraconazole analogues for hedgehog pathway inhibition

The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in embryonic development. While the pathway is generally quiescent during adult life, dysregulation of the Hh pathway can lead to cell proliferation and tumor growth. This abnormal Hh signaling is typically responsible for tumors associated with basal cell carcinoma (BCC) and medulloblastoma (MB) and inhibiting the Hh pathway is a valid target to develop novel chemotherapeutic agents. Most Hh inhibitors identified to date target the protein smoothened (SMO), a crucial component of the Hh pathway. Vismodegib is a SMO inhibitor that was recently approved by the FDA for the treatment of advanced BCC. However, there has been an emergence of resistance to Vismodegib; this resistance is a result of a point mutation in SMO. This occurrence of Vismodegib-resistant SMO mutations highlights the therapeutic need for new Hh pathway inhibitors. Itraconazole (ITZ), a well-known antifungal agent, was recently determined to be a potent inhibitor of the Hh pathway in vitro and in vivo; ITZ was also found to be a potent inhibitor of wild type SMO and Vismodegib-resistant SMO. ITZ is well-characterized and there is a good understanding of its potential side effects. This well-known safety profile makes ITZ a desirable drug candidate. Our ongoing studies on the ITZ scaffold are focused on exploring the regions of ITZ that are required for potent Hh pathway inhibition. The design, synthesis, and preliminary in vitro evaluation of these ITZ analogues will be reported herein. Citation Format: Jennifer Pace, M. Kyle Hadden. Synthesis and evaluation of itraconazole analogues for hedgehog pathway inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3666. doi:10.1158/1538-7445.AM2015-3666