GANT61 is an inhibitor for GLI1 as well as GLI2-induced transcription, inhibits hedgehog with IC50 of 5 μM, displays selectivity over other pathways, such as TNF and glucocorticoid receptor gene transactivation. GANT61 inhibits the DNA binding ability of GLI1. GANT61 inhibits hedgehog signaling with IC50 of 5 μM, displays selectivity over other pathways, such as TNF signaling/NFκB activation, glucocorticoid receptor gene transactivation, and the Ras–Raf–Mek–Mapk cascade. GANT61 efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner. GANT61 induces inhibition of DNA replication in early S-phase in human colon carcinoma cell lines, leading to DNA damage signaling involving an ATM–Chk2 axis and induction of cell death.
|Cell lines||HEK293 cells|
|Preparation method||HEK293 cells were transfected with GLI1 expression plasmid, together with the reporter plasmids 12xGliBS-Luc and R-Luc on 10-cm plates (day 0). Twenty-four hours later, cells were seeded in white 96-well plates with clear bottom at a density of 15,000 cells per well. Cells were allowed to attach, and compounds (Diversity Set, 1990 compounds; National Cancer Institute, Bethesda, MD) were added at a final concentration of 10 μM in DMSO (0.5% final DMSO concentration) (day 1.5). Cells were grown for another 24 h, subsequently lysed, and then analyzed by using the Dual Luciferase kit (Promega, Madison, WI). Plates were read on a Berthold Technologies (Bad Wildbad, Germany) microplate luminometer.|
|Incubation time||24 h|
|Animal models||22Rv1 cells xenograft in female BALB/c nude mice (nu/nu)|
|Formulation||corn oil:ethanol, 4:1|
|Dosages||50 mg/kg for 16 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft.
Fu J, et al. Cancer Lett. 2013 Mar 1;330(1):22-32. PMID: 23200667.
Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo.
Wickström M, et al. Int J Cancer. 2013 Apr 1;132(7):1516-24. PMID: 22949014.
Hedgehog signaling drives cellular survival in human colon carcinoma cells.
Mazumdar T, et al. Cancer Res. 2011 Feb 1;71(3):1092-102. PMID: 21135115.
Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.
Lauth M, et al. Proc Natl Acad Sci U S A. 2007 May 15;104(20):8455-60. PMID: 17494766.
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