title: Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier.
abstract: 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.
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego, California 92121, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Rohner
authors.forename: Mary E
authors.initials: ME
authors.lastname: Spilker
authors.forename: Justine L
authors.initials: JL
authors.lastname: Lam
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pascual
authors.forename: Darian
authors.initials: D
authors.lastname: Bartkowski
authors.forename: Qing John
authors.initials: QJ
authors.lastname: Li
authors.forename: Amy H
authors.initials: AH
authors.lastname: Yang
authors.forename: Greg
authors.initials: G
authors.lastname: Stevens
authors.forename: Meirong
authors.initials: M
authors.lastname: Xu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wells
authors.forename: Simon
authors.initials: S
authors.lastname: Planken
authors.forename: Sajiv
authors.initials: S
authors.lastname: Nair
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Sun
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D000072079:Patched Receptors; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1
chemical_list: C573117:1-(4-(5'-chloro-3,5-dimethyl-2,4'-bipyridin-2'-yl)piperazin-1-yl)-3-(methylsulfonyl)propan-1-one; D000970:Antineoplastic Agents; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D010879:Piperazines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D015082:2,2'-Dipyridyl