The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing growth and tissue patterning during embryonic development. Dysregulation of Hh signaling contributes to the development of a variety of human tumors, most notably basal cell carcinoma (BCC) and medulloblastoma (MB). A small molecule inhibitor of Hh signaling, GDC-0449, was recently approved for the treatment of advanced BCC, providing evidence that this pathway has clinical relevance. GDC-0449 binds and inhibits smoothened (Smo), a key regulator of the pathway that is the cellular target of multiple small molecule Hh pathway inhibitors in pre-clinical and clinical development; however, mutations in Smo resulted in forms of MB resistant to GDC-0449, highlighting the need for continued development of Hh pathway inhibitors. Itraconazole (ITZ), a member of the triazole class of antifungal agents, was recently identified as a potent inhibitor of Hh signaling in vitro and in vivo (IC50 values = 270 - 690 nM). Most importantly, ITZ maintains inhibitory activity against multiple mutant forms Smo that confer resistance to GDC-0449 and prolongs survival of mice with GDC-0449 resistant forms of MB. Despite its promising anti-Hh activity, ITZ exhibits poor solubility and inhibits CYP3A4, a detrimental side effect that results in multiple drug-drug interactions and requires careful monitoring of diet and drug regimens when ITZ is administered. Preliminary structure-activity relationship (SAR) studies for ITZ-mediated Hh inhibition performed in the Hadden lab have identified multiple regions of the ITZ scaffold that are amenable to modification. Our data suggests that further modifications to these regions will provide ITZ analogues that maintain potent or enhanced Hh inhibition, while also demonstrating improved pharmacokinetic parameters and reduced off-target side effects characteristic of ITZ treatment. The overall goal of the studies described in this proposal is to develop a class of improved Hh pathway inhibitors based on the ITZ scaffold as potential anti-cancer chemotherapeutics. With respect to this central tenet, a collaborative group of medicinal chemists and cancer biologists will undertake the following specific aims: (1) synthesize and characterize ITZ analogues designed to target the Hh signaling pathway, (2) evaluate the in vitro activity of ITZ analogues prepared in Aim 1, and (3) evaluate the in vivo activity of lead IT analogues in murine models of Hh-dependent cancer. The identification of ITZ as an Hh pathway inhibitor has opened a new avenue of exploration into potential therapeutic applications of this clinically efficacious antifungal and represents a unique scaffold for the design, synthesi, and evaluation of a new class of Hh pathway inhibitors.
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