Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts [1]. BMS-986195 is a highly potent, selective covalent, irreversible inhibitor of BTK with an IC50 value of 0.1 nM [1]. BMS-986195 was highly effective at inhibiting TNFα production with equivalent potency to those measured for the BCR-dependent end points in B cells. In human whole blood assays, it potently inhibited BCR-stimulated expression of CD69 on B cells with an IC50 of 11 nM [1]. When administered orally to BALB/c mice, BMS-986195 dose-dependently inactivated BTK in peripheral blood with a single dose of 0.5 mg/kg, providing 90% inactivation 4 h after dosing. In addition, BMS-986195 provided a dose-dependent protection against pitting, loss of bone mass, woven porous bone, and fusion of the small bones evident in the mice receiving only vehicle [1].
作用机制
The tetrahydrocarbazole NH and the carboxamide carbonyl of BMS-986195 are engaged in a hydrogen bonding interaction with Met477 in the hinge region of the active site of BTK .
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