Discovery of a Potent and Selective NF-κB-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo

Abstract

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.

Activation of NF-κB-Inducing Kinase in Islet β Cells Causes β Cell Failure and Diabetes

“…However, it should be noted that the in vivo pharmacokinetic properties of B022 are not good. 5,14 Therefore, multiple injections of B022 per day are required to achieve the in vivo inhibition of STZ-induced b cell death and hyperglycemia. To determine whether inhibition of NIK in b cells by small molecules can ameliorate diabetes in the chronic mouse models (e.g., multiple low-dose STZ injections or NOD mice), further modifications to B022 are required.…”

“…We recently reported that B022 is a specific inhibitor of NIK activity, and B022 can ameliorate CCl4-induced liver injury and inflammation in mice. 5,14 To determine whether inhibition of NIK activity by B022 can prevent NIK-induced b cell failure, we infected INS-1 832/13 cells with ad-NIK adenovirus in the presence of B022 for 16 h, after which p100-to-p52 processing, cell viability, and gene expression were measured. As expected, B022 (10 mM) completely blocked NIKinduced p100-to-p52 processing ( Figure 6A).…”

Targeting NF-κB Signaling for Multiple Myeloma

“…Recently, a novel NIK inhibitor called Cpd33 is reported to inhibit RANKL-induced osteoclastogenesis in an ovariectomized mouse model [ 84 ]. Oral administration of another NIK inhibitor XT2 in mice relieved toxin-induced liver inflammation [ 85 ]. These inhibitors may be tested in MM mouse models in the future.…”

“…In this regard, peptide inhibitors against L-plastin that inhibit osteoclast activity [ 102 , 115 ] might be tested. Alternatively, NIK inhibitors under development [ 82 , 83 ], or shown to repress inflammation in other mouse models [ 84 , 85 ], may be tested in MM mouse models too.…”

Noncanonical NF-κB Signaling Pathway in Liver Diseases

“…At the same time, selective small-molecule NIK inhibitor 46 (XT2) or B022 are effective at inhibiting drug-induced liver injury and liver inflammation, which shows that NIK is an attractive drug target in drug-induced liver diseases. 38,61 Autoimmune liver disease…”