Uses
PF-5274857 is a potent and selective Smoothened (Smo) antagonist, inhibits Hedgehog (Hh) signaling, respectively, and can penetrate the blood–brain barrier.
Biological Activity
pf-5274857 is an inhibitor of hedgehog (hh) signaling pathway and is identified as a potent and selective antagonist of smoothened (smo) with an ic50 of 5.8 nm.smoothened, a g protein-coupled receptor, is a component of the hedgehog signaling pathway and is conserved from flies to humans. this protein is the molecular target of the teratogen cyclopamine. smo can act as an oncogene and the activation of smo mutations leads to unregulated activation of the hedgehog pathway and cancer.in mef cells, treatment of pf-5274857 completely blocked shh-induced hh pathway activity, which was measured by the transcriptional activity of smo downstream gene gli1.
Enzyme inhibitor
This brain-penetrating Smoothened (Smo) antagonist (FW = 436.96 g/mol; CAS 1373615-35-0), also known as 1-(4-(5-chloro-4-(3,5-dimethylpyridin- 2-yl)pyridin-2-yl)piperazin-1-yl)-3-(methylsulfonyl)propan-1-one, potentlyand selectively inhibits Hedgehog (Hh) signaling (IC50 = 5.8 nM; Ki = 4.6 nM). PF-5274857 elicits robust antitumor activity in a mouse model of medulloblastoma (IC50 = 8.9 nmol/L), with down-regulation of Gli1, a marker closely linked to the tumor growth inhibition in patched (+/-) medulloblastoma mice. PF-5274857 also inhibits Smo activity within the brain of primary medulloblastoma mice, improving survival. PF-5274857 is orally available and metabolically stable in vivo. Other Hedgehog inhibitors include: GANT61, BMS-833923, Purmorphamine, SANT-1, LY2940680, Cyclopamine, LDE225 (or NVP-LDE225, Erismodegib), Vismodegib (GDC-0449)
in vivo
pf-5274857 showed anti-tumor activity in a mouse medulloblastoma model with ic50 of 8.9 nm. pf-5274857 also shows significant dose-dependent tumor growth inhibition (tgi) and induces tumor regression. in skin tissue, downregulation of gli1 and gli2 is also observed with a similar time course by pf-52748571.
References
1. rohner a, spilker me, lam jl, et al. effective targeting of hedgehog signaling in a medulloblastoma model with pf-5274857, a potent and selective smoothened antagonist that penetrates the blood-brain barrier. molecular cancer therapeutics.2012;11(1):57-65.
