Hedgehog (Hh) signaling normally functions to specify embryonic pattern by directing cellular differentiation and proliferation, whereas aberrant Hh pathway activation is associated with the formation of tumors such as basal cell carcinoma and medulloblastoma. Cellular responses to the secreted Hh polypeptide are mediated by Patched (Ptc) and Smoothened (Smo). SANT-1 is a structurally unrelated Smo antagonist with IC50 value of 20 nM[2]. In vitro, SANT-1 at concentration of 10 μM efficiently inhibited cyclopamine and jervine induced translocation of Smo to the primary cilium in MEFs[1]. SANT-1 inhibited most NSCLC cell lines with IC50 value of 40 μM. Treatment of the EGFR-TKI-resistant cell lines H1975 and A549 with 40 μM SANT-1 for 24h downregulated GLI1 expression and weakened Snail expression, but did not inhibit clonogenic growth. The combination of 40 μM gefitinib and 40 μM SANT-1 synergistically inhibited tumorigenesis and proliferation in EGFR-TKI-resistant NSCLC cell lines H1975 and A549{{Bai XY, Zhang XC, Yang SQ, et al. Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines. PLoS One. 2016;11(3):e0149370|https://www.ncbi.nlm.nih.gov/pubmed/26943330
}}. In vivo, the leukaemia burden was reduced in mice receiving the 1 μM Vorinostat and 2.5 μM SANT-1 treated OCI-AML3 cells[3].
作用机制
SANT-1 binds to a narrow and deep hydrophobic cavity in its 7 transmembrane (TM) domain of Smol[4].
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