Abstract
Abstract Inappropriate regulation of the hedgehog (Hh) signaling pathway contributes to the development and progression of a number of human cancers; most notably, basal cell carcinoma (BCC) and medulloblastoma (MB). Clinical validation of small molecule mediated silencing of the Hh pathway was recently demonstrated by the FDA approval of vismodegib for the treatment of locally advanced BCC, representing a first-in-class inhibitor of the Hh signaling pathway. Vismodegib antagonizes Hh signaling by directly binding smoothened (SMO), a critical regulator of the pathway and target of numerous small molecule preclinical and clinical drug candidates. Vismodegib treatments in MB patients revealed novel SMO mutants that demonstrated resistance to vismodegib therapy, which underscores the need for continued development of novel Hh pathway inhibitors. Recently, itraconazole (ITZ) was identified as an inhibitor of Hh signaling in vitro and in vivo. Characterization indicated ITZ, a clinically used antifungal agent, maintains Hh inhibition against vismodegib-resistant SMO mutants. Ongoing structure-activity analysis for the ITZ scaffold is currently being investigated to identify analogues with improved potency and reduced non-specific toxicity. Results from these studies to identify candidates with improved pharmacological profiles and selectivity for Hh signaling modulation will be described herein. Citation Format: Albert M. DeBerardinis, M. Kyle Hadden. Reconstructing the itraconazole scaffold towards improved specificity for hedeghog signaling 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 3665. doi:10.1158/1538-7445.AM2015-3665
Published Version
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