Development Of Covalent Inhibitors Targeting BTK

Cancer is one of the major public health issues of common concern.The incidences of lymphoma and leukemia are also on the rise every year,these cancers affect people’s normal life.Bruton’s tyrosine protein kinase have been reported,it is the ideal target for treat these lymphoma.BTK plays an important role in the B lymphocyte cell lines.CNX-774 is a covalent inhibitor targeting BTK,in order to improve the activity and explore the effect of warheads in different BTK-related cell lines,design and synthesized novel warheads,a series of analogues were obtained via simple modifications of CNX-774.All inhibitors were evaluated on IgE multiple myeloma cell line at 200 nmol/L^-1.And screened compounds were further tested on8226 MM,Ramos,HBL-1,HeLa cell lines and so on,and metabolic stability of inhibitors were evaluated.It was showed that compounds RA-1 and RA-3 were the most two potent BTK inhibitors.Compared to CNX-774,they showed more excellent inhibition to BTK-related tumor cell lines,and possessed similar or even lower cytotoxicity.Molecular docking assisted to screen BTK inhibitors,the docking results could explain the interaction between analogues of CNX-774 and BTK.New covalent inhibitors targeting BTK were selected via these methods.