Design, synthesis and biological evaluation of novel dithiocarbamate-substituted diphenylaminopyrimidine derivatives as BTK inhibitors

Abstract Bruton’s tyrosine kinase (BTK) had emerged as an attractive target related to B-lymphocytes dysfunctions, especially hematologic malignancies and autoimmune diseases. In our study, a series of diphenylaminopyrimidine derivatives bearing dithiocarbamate moieties were designed and synthesized as novel BTK inhibitors for treatment of B-cell lymphoma. Among all these compounds, 30ab (IC50 = 1.15 ± 0.19 nM) displayed similar or more potent inhibitory activity against BTK than spebrutinib (IC50 = 2.12 ± 0.32 nM) and FDA approved drug ibrutinib (IC50 = 3.89 ± 0.57 nM), which was attributed to close binding of 30ab with BTK predicted by molecular docking. In particular, 30ab exhibited enhanced anti-proliferative activity against B-lymphoma cell lines at the IC50 concentration of 0.357 ± 0.02 μM (Ramos) and 0.706 ± 0.05 μM (Raji) respectively, almost 10-fold better than ibrutinib and spebrutinib. In addition, 30ab displayed stronger selectivity on B-cell lymphoma over other cancer cell lines than spebrutinib. Furthermore, 30ab efficiently blocked BTK downstream pathways and resulted in apoptosis of cancer cells. In vivo xenograft model evaluation demonstrated the significant efficacy and broad safety margin of 30ab in treatment of B-cell lymphoma. We proposed that compound 30ab was a candidate for further study and development based on our preliminary findings.