Preclinical and clinical studies have shown that itraconazole functions as a potent inhibitor of both Hedgehog pathway signaling and angiogenesis. Most importantly, itraconazole maintains inhibitory activity against multiple forms of smoothened (SMO) that confer resistance to vismodegib and prolong survival of mice with vismodegib-resistant forms of medulloblastoma. Preliminary structure-activity relationship (SAR) studies for itraconazole-mediated Hedgehog pathway inhibition and angiogenesis performed in the Hadden laboratory at the University of Connecticut have identified multiple regions of the itraconazole scaffold that are amenable to modification. The data suggest that these itraconazole analogues maintain potent Hh inhibition, while also demonstrating improved pharmacokinetic (PK) parameters and reduced off-target side effects characteristic of current itraconazole formulations for treatment of cancer.
INHIBITOR is collaborating with Dr. Hadden’s laboratory to study the efficacy and safety of a key itraconazole analogue as an inhibitor to the formation and growth of human basal cell carcinoma (BCC) tumors in a xenograph mouse model. Should this effort demonstrate anti-tumor effects for BCC, INHIBITOR will expand pre-clinical testing and broaden the scope of the collaboration with a goal toward future Phase 1 testing to determine dosing and safety in humans.