Aberrant stabilization and activation of NIK correlates with an augmented activity of NF-κB2, which is often associated with atuoimmune diseases, inflammatory diseases, and cancer. Therefore, the inhibition of NIK has been pursued as an attractive strategy for treatment of certain diseases such as systemic lupus erythematosus, inflammatory disease, multiple myeloma, and pancreatic cancer. Herein, we report our efforts to design and synthesis of novel and potent small molecules inhibitors of NIK. Our lead compounds is characterized by a novel pyrrolo[3,2-d]pyrimidin core structure, which shows potent inhibition of NF-κB2 signal pathway in intact cells. Our data show that the lead compound 1 has an IC50 value in nM range in inhibition of NIK kinase activity. It has also been found that 1 was active in MM.1S cancer cells and caused changes of gene expression level of c-Myc, p21, and p100 .

Discovery of pyrrolo[3,2-d]pyrimidine-containing compounds as inhibitors of NIK kinase

2019 Fall National Meeting

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