Smoothened (SMO) is a GPCR-like receptor which, with Patched, mediates hedgehog signaling to regulate gene expression through the Gli transcription factors. SANT 1 is a potent inhibitor of hedgehog signaling that acts by directly antagonizing SMO (IC50 = 20 nM). It counteracts SMO activation by the SMO agonist SAG but only partially competes with SAG binding to SMO. SANT 1 targets inactive SMO while it is in the cytoplasm, before it relocates to the primary cilium and is activated. Through antagonism of SMO, SANT 1 represses Gli-mediated transcription in a variety of cell types.
Treatment of Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma cells2 and chronic lymphocytic leukemia cells3 with SANT-1 induced cell death.
A potent antagonist of the sonic hedgehog (Shh) signaling pathway (IC50=20nm inShh-LIGHT2 assay an d in Ptch1-/- cells) that acts by binding to smoothened (Smo: KD=1.2 nM), a distant relative of G protein-coupled receptors. In contrast to cyclopamine, SNAT-1 inhibits the activities of both wild type and oncogenic Smo with equal potency (IC50=30nm in SmoA1-LIGHT2 assay).
ChEBI: 1-(3,5-dimethyl-1-phenyl-4-pyrazolyl)-N-[4-(phenylmethyl)-1-piperazinyl]methanimine is a ring assembly and a member of pyrazoles.
Potent, cell-permeable inhibitor of Sonic hedgehog (Shh) signaling; high affinity antagonist of smoothened activity (K D = 1.2 nM). Inhibits smoothened agonist effects with an IC 50 of 20 nM (in Shh-LIGHT2 cells).
SANT-1 is a potent sonic hedgehog pathway (Shh) antagonist that directly inhibits by binding to the smoothened (Smo) receptor. SANT-1 inhibits wild type and oncogenic Smo with equal potency.
[1]. chen j k., taipale j, young k e,. small molecule modulation of smoothened activity. proc natl acad sci u s a, 2002, 99: 14071-6.
[2]. chun sg, zhou w & yee n s. combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. cancer biol ther, 2009, 8: 1328-39.
