Design and synthesis of novel substituted benzyl pyrrolopyrimidine derivatives as selective BTK inhibitors for treating mantle cell lymphoma.

Ibrutinib, a potent irreversible Bruton's tyrosine kinase (BTK) inhibitor, was approved by the FDA for treating mantle cell lymphoma (MCL). Although ibrutinib exhibited excellent antitumor activity, it was associated with certain adverse reactions, with off-target effects against EGFR, Itk and Src family kinases. Our studies yielded a novel series of substituted benzyl pyrrolopyrimidine derivatives capable of potent inhibition of BTK. Compared with ibrutinib, compound 15c exhibited potent BTK inhibitory activity and enhanced antiproliferative activity, a 12-24-fold increase, against MCL cell lines, with IC50 values lower than 1 µM. Low micromolar doses of 15c inhibited the BCR signaling pathway and strongly induced the apoptosis of Z138 cells. Ibrutinib and 15c induced autophagy in a dose-dependent manner in Z138 cells. Moreover, compound 15c induced the production of reactive oxygen species (ROS), which may be a reason for its potent antiproliferative activity. Importantly, compound 15c showed greater BTK selectivity than ibrutinib, indicating a potentially safer treatment of MCL.