Wnt signaling is tightly controlled during cellular proliferation, differentiation, and embryonic morphogenesis. Aberrant activation of this pathway plays a critical role in a variety of cancers, such as cutaneous squamous cell carcinoma (SCC), breast cancer, and colorectal cancer[2]. GNF-6231 is a potent, selective, and orally bioavailable Porcupine inhibitor that blocks Wnt signaling with an IC50 value of 0.8 nM[2]. GNF-6231 shows IC50s of greater than 10 μM on all CYP (cytochromes P450) isoforms tested (2C9, 2D6, 3A4) and high permeability in a Caco-2 human cell permeability assay[2]. GNF-6231 is moderately bound to mouse, rat, dog, monkey, and human plasma proteins (88.0, 83.1, 90.9, 71.2, and 95%, respectively) as determined by rapid equilibrium dialysis. It shows good oral bioavailability, ranging from 72 to 96% in preclinical species (mouse, rat, and dog) when dosed in solution formulations. GNF-6231 is expected to have minimal to marginal distribution to tissues compared to total body water following intravenous administration to mouse (Vss 0.57 L/kg), rat (Vss 0.70 L/kg), and dog (Vss 0.25 L/kg). Treatment with GNF-6231 in MMTV-Wnt1 subcutaneously implanted tumor bearing mice led to pronounced inhibition of the Wnt signaling activity as measured by the reduction of Wnt target gene Axin2 expression[2].
GNF-6231 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Sca1+CD31−CD45− cells
100 nM
24 hours
To evaluate the effect of GNF-6231 on the proliferation of Sca1+ cardiac progenitor cells. Results showed that WNT inhibition increased proliferation of Sca1+ cardiac progenitors.
Cell Stem Cells Regen Med. 2016 Nov;2(2):10
GNF-6231 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mouse
MMTV-Wnt1 xenograft tumor model
Oral
0.3, 1, 3 mg/kg
Once daily for 2 weeks
Evaluate the antitumor efficacy of GNF-6231 in the MMTV-Wnt1 tumor model, showing significant tumor growth inhibition at 0.3 mg/kg and tumor regression at 1 and 3 mg/kg
ACS Med Chem Lett. 2016 May 10;7(7):676-80
C57Bl/6 mice
Myocardial infarction model
Intravenous injection
5 mg/kg
Once daily for 6 days
To evaluate the effect of GNF-6231 on cardiac function and remodeling post-MI. Results showed that GNF-6231 treatment significantly reduced the decline in cardiac function, prevented adverse cardiac remodeling, and reduced infarct size.
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