Structure-based optimization of indoline-containing compounds as second generation inhibitors of NF-KB-inducing kinase (NIK)

Overactivation of NIK led to increased transcriptional activity of NF-KB2, which was associated with human metabolic diseases, immunological disorders, and cancer. Therefore, NIK inhibitors were pursued as a potential treatment of NIK-driven human diseases. The first generation of NIK inhibitors features propargylic alcohol moieties, which were metabolic soft spots that led to the discovery of a second generation of NIK inhibitors without a propargylic alcohol. In this study, a series of compounds were designed, synthesized, and evaluated as novel NIK inhibitors using a NIK kinase assay. To evaluate selectivity profiles of these inhibitors, the most potent compound 50 was tested over COT and other two panels of 31 kinases. In addition, 50 inhibited NIK-driven upregulation of CCL5 gene in primary hepatocytes and showed low cytotoxicity against normal kidney cells HEK-293. These attributes make 50 a promising candidate for future optimization aimed to increase potency and selectivity against NIK and NF-KB2 pathway.