Objective:B-cell antigen receptor(BCR)signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies.Bruton tyrosine kinase(BTK),a critica...Objective:B-cell antigen receptor(BCR)signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies.Bruton tyrosine kinase(BTK),a critical mediator of BCR signaling,is an attractive target for the treatment of B-cell malignancies.This study aimed to identify a highly potent and selective BTK inhibitor.Methods:Homogeneous time-resolved fluorescence assays were used to screen BTK inhibitors.Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the BCR signaling pathway.Additionally,the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine B-cell lymphoma.Results:We found a novel irreversible and non-competitive inhibitor of BTK,SY-1530,which provided dose-dependent and timedependent inhibition.SY-1530 selectively bound to BTK rather than inducible T-cell kinase;consequently,it did not significantly affect T-cell receptor signaling and caused limited off-target effects.SY-1530 blocked the BCR signaling pathway through downregulation of BTK activity,thus leading to impaired phosphorylation of BTK and its downstream kinases.Moreover,SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of B-cell malignancy(P<0.001).SY-1530 also induced positive clinical responses in spontaneous canine B-cell lymphoma.Conclusions:SY-1530 is an irreversible and selective BTK inhibitor that shows inhibitory effects on B-cell malignancies by blocking the BCR signaling pathway.Therefore,it may be a promising therapeutic approach for the treatment of B-cell malignancies.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81622037,81672762,and 81372185)and the Beijing Natural Science Foundation(Grant No.5194023).
文摘Objective:B-cell antigen receptor(BCR)signaling is required to maintain the physiological functions of normal B cells and plays an important pathogenic role in B-cell malignancies.Bruton tyrosine kinase(BTK),a critical mediator of BCR signaling,is an attractive target for the treatment of B-cell malignancies.This study aimed to identify a highly potent and selective BTK inhibitor.Methods:Homogeneous time-resolved fluorescence assays were used to screen BTK inhibitors.Typhoon fluorescence imaging and Western blot analysis were used to confirm the effects of SY-1530 on the BCR signaling pathway.Additionally,the anti-tumor activities of SY-1530 were evaluated in TMD8 xenografts and spontaneous canine B-cell lymphoma.Results:We found a novel irreversible and non-competitive inhibitor of BTK,SY-1530,which provided dose-dependent and timedependent inhibition.SY-1530 selectively bound to BTK rather than inducible T-cell kinase;consequently,it did not significantly affect T-cell receptor signaling and caused limited off-target effects.SY-1530 blocked the BCR signaling pathway through downregulation of BTK activity,thus leading to impaired phosphorylation of BTK and its downstream kinases.Moreover,SY-1530 induced apoptosis in a caspase-dependent manner and efficaciously inhibited tumor growth in mouse xenograft models of B-cell malignancy(P<0.001).SY-1530 also induced positive clinical responses in spontaneous canine B-cell lymphoma.Conclusions:SY-1530 is an irreversible and selective BTK inhibitor that shows inhibitory effects on B-cell malignancies by blocking the BCR signaling pathway.Therefore,it may be a promising therapeutic approach for the treatment of B-cell malignancies.
