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].
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