Design, synthesis, and biological evaluation of cyano-substituted 2,4-diarylaminopyrimidines as potent JAK3 inhibitors for the treatment of B-cell lymphoma.

A series of cyano-substituted 2,4-diarylaminopyrimidines was designed and synthesized as potent non-covalent JAK3 inhibitors. Among the derivatives synthesized, 9o (IC50 = 22.86 nM), 9 k (IC50 = 21.58 nM), and 9j (IC50 = 20.66 nM) demonstrated inhibitory potencies against JAK3 similar to the known JAK3 inhibitor tofacitinib (IC50 = 20.10 nM). Moreover, 9o displayed potent anti-proliferative activities against Raji and Ramos cells, with IC50 values of 0.9255 μM and 1.405 μM, respectively. In addition, 9o demonstrated low toxicity in normal HBE (human bronchial epithelial cells, IC50 > 10 μΜ) and L-02 (human liver cells, IC50 = 3.104 μΜ) cells. Analysis of the mode of action by flow cytometry indicated that 9o effectively arrested Raji cells at the G2/M phase. Taken together, these results suggested that 9o might be a promising candidate for development as a potential treatment for B-cell lymphoma.