GNF-6231 is a potent, orally active and selective Porcupine inhibitor with IC50 of 0.8 nM.
GNF-6231 shows a good solubility. It has no appreciable activities, at least up to 10 μM testing concentrations, for more than 200 off-targets, which include GPCRs, kinases, proteases, transporters, ion channels, and nuclear receptors. GNF-6231 shows IC50s of greater than 10 μM on all CYP isoforms tested (2C9, 2D6, 3A4). It shows high permeability in a Caco-2 human cell permeability assay with a possible efflux[1].
GNF-6231 demonstrates excellent pathway inhibition and induces robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model. 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). 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)[1].
[1] Cheng D, et al. ACS Med Chem Lett. 2016, 7(7):676-80.