Uses
GANT 58 is an inhibitor of GLI1-induced transcription. This affects the functional aspects of cell growth, differentiation and activation. The modulatory ability of this drug is critical to maintenance of self-tolerance, immune suppression and tumor immunosurvelliance involved in T regulatory cells. GANT58 also inihibits hedgehog signalling inducing apoptosis in acute T cell leukemia cells.
Definition
ChEBI: 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine is a member of pyridines.
Biological Activity
gant 58 is an antagonist of gli that inhibits gli1-induced transcription with an ic50 value of 5 μm [1].gli1 is a human glioblastoma isolated protein which belongs to gli protein family. gli proteins act as effectors in hedgehog signaling pathway and get involved in cell proliferation, determination and patterning during embryo development.gant 58 is considered to inhibit gli1-mediated gene trans-activation with a high selectivity for hedgehog signaling pathway. when tnf signaling/nfkb activation, glucocorticoid, receptor gene transactivation, and the ras-raf-mek-mapk cascade were treated with gant 58, no inhibition was observed. when sag-treated shh-l2 cells were treated with 10 μm gant 58 for 48 hr, the reduction of hedgehog pathway signaling was observed, whereas gli1 mrna level reduction was induced by the treatment of 10 μm gant 58 for 2-3 days. indeed, gant 58 was confirmed as inhibitor of hedgehog signaling pathway downstream sufu and smo [1]. furthermore, gant 58 treatments for 48 hr resulted in the significant reduction of cell viability in a dose-dependent manner for ccrfecem, cem7e14, cem1e15 and jurkat cells. when ccrfecem cells were treated with 10 μm gant 58 for 48 hr, the percentage of cells in g1/s phase increased whereas the percentage in g2/m phase decreased [2].in mouse model with xenograft, daily s.c. injection of gant 58 resulted in significant suppression of tumor cell growth. 50 mg/kg/d gant 58 injections for 18 days induced the suppression of additional xenograft growth and restrict the increase of tumor size. no side effects were observed during the treatment [1].
in vivo
Nude mice are injected s.c. with GLI1-positive 22Rv1 prostate cancer cells, and tumors are established (median size ≈250 mm3). Nude mice are treated with daily s.c. injections at a concentration of 50 mg/kg of cyclopamine, GANT61, GANT58, or solvent only (n=4-5 for each group). However, after 3 days, cyclopamine-treated animals presented with severe ulcerations at the injection sites. Therefore, changing the treatment regimen to injections only every second day. To be able to compare all compounds, this protocol is also introduced for the GANTs, although mice treated with these compounds showed no such signs of toxicity. All injections are done 2-3 cm away from the tumors. During an 18-day treatment period, suppression of tumor cell growth is observed for all compounds. Treatment with cyclopamine or GANT58 results in the inhibition of additional xenograft growth and limited the increase in tumor size[1].
References
[1] lauth m, bergstr?m ?sa, shimokawa t, toftg?rd r. inhibition of gli-mediated transcription and tumor cell growth by small-molecule antagonists.?proceedings of the national academy of sciences of the united states of america. 2007,104(20):8455-8460.
[2] hou x, chen x, zhang p, et al. inhibition of hedgehog signaling by gant58 induces apoptosis and shows synergistic antitumor activity with akt inhibitor in acute t cell leukemia cells. biochimie. 2014, 101:50-9
