Bruton’s tyrosine kinase (BTK), a member of the Tec family of tyrosine kinases and expressed in B cells, macrophages, and monocytes but not in T cells, plays a crucial role in signaling through the B cell receptor (BCR) and the Fcγ receptor (FcγR) in B cells and myeloid cells, respectively[3]. Poseltinib, an orally active, selective and irreversible BTK inhibitor with an IC50 value of 1.95 nM[4]. Poseltinib effectively suppressed splenic B220+GL7+, B220+CD138+, and B220+CD69+B cell counts, and anti-dsDNA IgG and reduced splenomegaly and lymph node enlargement. It also prevented skin lesions caused by lupus development, ameliorated renal inflammation and damage with increased blood urea nitrogen and creatinine, and decreased proteinuria. Furthermore, Poseltinib also decreased mortality from lupus development in both mouse models. Those results indicated that inhibition of BTK by Poseltinib effectively reduced B cell hyperactivity and significantly attenuated the development of SLE (Systemic lupus erythematosus) and LN (lupus nephritis) in rodent SLE models[4].
作用机制
Poseltinib may covalently bind to the active site (cysteine 481 residue) of BTK.
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