Discovery of novel ibrutinib analogues to treat malignant melanoma.

A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7, exhibited strong antiproliferative activity in all cell lines, and its IC50 value in B16 cells was almost 9-fold better than that of ibrutinib. Mechanism of action studies showed that YL7 inhibited proliferation and migration and induced G1 cell cycle arrest, apoptosis and autophagy in B16 cells. Further assessment of in vivo antitumor efficacies demonstrated that YL7 significantly inhibited the growth of B16 melanoma. These preliminary studies suggest that it is reasonable to modify the structure of ibrutinib for antimelanoma treatment.