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Effective Targeting of Hedgehog Signaling in a Medulloblastoma Model with PF-5274857, a Potent and Selective Smoothened Antagonist That Penetrates the Blood–Brain Barrier

Inhibition of the Smoothened (Smo) represents a promising therapeutic strategy for treating malignant tumors that are dependent on the Hedgehog (Hh) signaling pathway. PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a Ki of 4.6 ± 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC50 of 2.7 ± 1.4 nmol/L in cells. This Smo antagonist showed robust antitumor activity in a mouse model of medulloblastoma with an in vivo IC50 of 8.9 ± 2.6 nmol/L. The downregulation of Gli1 is closely linked to the tumor growth inhibition in patched+/− medulloblastoma mice. Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched+/− medulloblastoma tumor models yielded similar tumor and skin Gli1 IC50 values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels. In addition, PF-5274857 was found to effectively penetrate the blood–brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. The brain permeability of PF-5274857 was also confirmed and quantified in nontumor-bearing preclinical species with an intact blood–brain barrier. PF-5274857 was orally available and metabolically stable in vivo. These findings suggest that PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway. Mol Cancer Ther; 11(1); 57–65. ©2011 AACR.