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GDC-046 is a potent, selective, and orally bioavailable TYK2 inhibitor with Kis of 4.8, 0.7, 0.7, and 0.4 nM for TYK2, JAK1, JAK2, and JAK3, respectively[1].

In cell-based assays, GDC-046 demonstrates reasonable potency in blocking the IL-12 pathway (IL-12 pSTAT4 EC50=380 nM) while displaying less activity in the EPO (JAK2) pathway (EPO pSTAT5 EC50=1700 nM) and IL-6 (JAK1) pathway (IL-6 pSTAT3 EC50=2000 nM)[1].

In mice, GDC-046 exhibits relatively high clearance (65 mL/min/kg) when dosed intravenously (i.v. 1 mg/kg) and exhibits modest oral exposure (AUC=2.6 μM.h at p.o. 5 mg/kg)[1].

[1]. Jun Liang, et al. Lead Optimization of a 4-aminopyridine Benzamide Scaffold to Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors. J Med Chem. 2013 Jun 13;56(11):4521-36.

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