TY - JOUR T1 - SY-1530, a highly selective BTK inhibitor, effectively treats B-cell malignancies by blocking B-cell activation JF - Cancer Biology & Medicine JO - Cancer Biology & Medicine SP - 995 LP - 1007 DO - 10.20892/j.issn.2095-3941.2020.0291 VL - 19 IS - 7 AU - Liao Wang AU - Yinghui Sun AU - Xijie Liu AU - Hongjuan Li AU - Chang Lu AU - Ronghui Yang AU - Chuanzhen Yang AU - Binghui Li Y1 - 2022/07/15 UR - http://www.cancerbiomed.org/content/19/7/995.abstract N2 - 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. ER -