Synthesis and biological activity of imidazole group-substituted arylaminopyrimidines (IAAPs) as potent BTK inhibitors against B-cell lymphoma and AML

Bruton's tyrosine kinase (BTK) is a member of the Tee kinase family and plays a key role in the modulation of the B-cell receptor (BCR)-mediated signaling pathway. Inhibition of BTK has been proven to be an effective therapeutic approach for various hematological malignancies, such as chronic lymphocytic leukemia (CLL), mantle cell leukemia (MCL), diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). Here, a new series of imidazole group-substituted arylaminopyrimidines (IAAPs) were designed and synthesized as potent inhibitors of the enzymatic activity of BTK with a half maximal inhibitory concentration (IC50) ranging from 13.10 to 42.40 nM. In particular, 11a and 11b exhibited stronger antiproliferative activity against AML and B lymphomas cell lines compared with BTK inhibitor ibrutinib and showed low cytotoxicity against normal peripheral blood mononuclear cells (PBMCs). In addition, analysis of the mechanism of action of these compounds revealed that 11a and 11b induced significant apoptosis in AML and B lymphoma cells by arresting the cell cycle at the G1/G0 or G2/M stage and blocked BTK autophosphorylation as well as the ensuing abrogation of prosurvival AKT and ERK signaling. Taken together, these results suggest that 11a and 11b might serve as valuable preclinical candidates for the treatment of AML and B-cell lymphoma.

Automated summary

A new series of BTK inhibitors, IAAPs, show promising anti-proliferative activity against AML and B-cell lymphoma cell lines with low cytotoxicity. Compounds 11a and 11b induced significant apoptosis in these cells by arresting the cell cycle and blocking BTK autophosphorylation and prosurvival signaling. These findings suggest that 11a and 11b may be valuable preclinical candidates for the treatment of AML and B-cell lymphoma.