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 time-dependent 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 down-regulation 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.

Liao Wang;Yinghui Sun;Xijie Liu;Hongjuan Li;Chang Lu;Ronghui Yang;Chuanzhen Yang;Binghui Li

Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China;Advanced Innovation Center for Human Brain Protection,Capital Medical University,Beijing 100069,China;Shouyao Holdings Co.,Ltd,Beijing 100195,China

癌症生物学与医学（英文版）

[1]Liao Wang;Yinghui Sun;Xijie Liu;Hongjuan Li;Chang Lu;Ronghui Yang;Chuanzhen Yang;Binghui Li-.SY-1530, a highly selective BTK inhibitor, effectively treats B-cell malignancies by blocking B-cell activation)[J].癌症生物学与医学（英文版）,2022(07):995-1007

TMD8

SY,highly,BTK,effectively,treats,malignancies,by,blocking,activation,Objective,antigen,receptor,BCR,signaling,required,maintain,physiological,functions,normal,cells,plays,important,pathogenic,role,Bruton,tyrosine,critical,mediator,attractive,target,treatment,This,study,aimed,identify,potent,Methods,Homogeneous,resolved,fluorescence,assays,were,screen,inhibitors,Typhoon,imaging,blot,analysis,confirm,effects,pathway,Additionally,tumor,activities,evaluated,xenografts,spontaneous,canine,lymphoma,Results,found,novel,irreversible,competitive,which,provided,dose,dependent,inhibition,selectively,bound,rather,than,inducible,consequently,did,not,significantly,affect,caused,limited,off,blocked,through,regulation,activity,thus,leading,impaired,phosphorylation,its,downstream,kinases,Moreover,induced,apoptosis,caspase,manner,efficaciously,inhibited,growth,mouse,models,malignancy,also,positive,clinical,responses,Conclusions,that,shows,inhibitory,Therefore,may,be,promising,therapeutic,approach

0.532288