The
overexpression of NIK plays a critical role in liver inflammatory
diseases. Treatment of such diseases with small-molecule NIK inhibitors
is a reasonable but underexplored approach. In this paper, we reported
the discovery of a potent and selective NIK inhibitor 46 (XT2). 46 inhibited the NIK kinase with an IC50 value of 9.1 nM in vitro, and it also potently suppressed NIK activities
in intact cells. In isogenic primary hepatocytes, treatment of 46 efficiently suppressed the expressions of NIK-induced genes. 46 was orally bioavailable in mice with moderate systemic
exposure. In a NIK-associated mouse liver inflammation model, 46 suppressed CCl4-induced upregulation of ALT,
a key biomarker of acute liver injury. 46 also decreased
immune cell infiltration into the injured liver tissue. Overall, these
studies provide examples that an NIK inhibitor is able to suppress
toxin-induced liver inflammations, which indicates its therapeutic
potentials for the treatment of liver inflammatory diseases.