RGD Reference Report - Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier.

General

Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier.
Authors:	Rohner, Allison Spilker, Mary E Lam, Justine L Pascual, Bernadette Bartkowski, Darian Li, Qing John Yang, Amy H Stevens, Greg Xu, Meirong Wells, Peter A Planken, Simon Nair, Sajiv Sun, Shaoxian
Citation:	Rohner A, etal., Mol Cancer Ther. 2012 Jan;11(1):57-65. doi: 10.1158/1535-7163.MCT-11-0691. Epub 2011 Nov 14.
RGD ID:	150521622
Pubmed:	PMID:22084163 (View Abstract at PubMed)
DOI:	DOI:10.1158/1535-7163.MCT-11-0691 (Journal Full-text)
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 K(i) of 4.6 ± 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC(50) 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 IC(50) 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 IC(50) 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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
medulloblastoma	treatment	ISO	Smo (Mus musculus)	150521622; 150521622		RGD
medulloblastoma	treatment	IMP		150521622		RGD

Objects Annotated

Genes (Rattus norvegicus)

Smo (smoothened, frizzled class receptor)

Genes (Mus musculus)

Smo (smoothened, frizzled class receptor)

Genes (Homo sapiens)

SMO (smoothened, frizzled class receptor)

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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.