BMS-986142 is a potent and highly selective reversible BTK inhibitor (IC50: 0.5 nM).

TEC:10 nM (cell free), ITK:15 nM (cell free), BMX:32 nM (cell free), TXK:28 nM (cell free), BTK:0.5 nM (cell free), BLK:23 nM (cell free)

针对一组384种激酶，BMS-986142展现出高度选择性，仅有五种其他激酶（Tec, ITK, BLK, Txk, BMX）的抑制作用<100倍选择性针对BTK。其中四种是Tec家族激酶，BTK即为该家族成员，仅有Tec（IC50: 10 nM）相对于BTK的抑制选择性<30倍。BMS-986142不抑制CD40L诱导的外周血B细胞CD86或CD69表达（对两者的IC50>10,000 nM）。当Ramos B细胞经抗IgM处理激活BCR时，BMS-986142抑制BTK依赖的钙离子通量（IC50: 9 nM）[2]。

BMS-986142以4、10和30 mg/kg剂量依次产生26%、43%和79%的剂量依赖性临床明显疾病减少。值得注意的是，与MTX单独使用相比，4 mg/kg BMS-986142联合MTX使用时可提供额外的临床评分效益（54%的抑制）而MTX单独使用的抑制率为19%。BMS-986142与MTX共同使用时，4 mg/kg剂量可以与MTX相比，将炎症和骨吸收减少53%，而单独使用任一化合物时分别只能减少24%和10%。此外，使用10和30 mg/kg BMS-986142显著抑制血清抗II型胶原蛋白IgG滴度。延迟至第21天的胶原增强剂后开始给药时，BMS-986142也显示出剂量依赖性的临床评分减少。在此治疗剂量方案中，BMS-986142的2、4和25 mg/kg剂量在研究结束时分别实现了17%、37%和67%的临床评分减少[2]。

Male DBA/1 mice are injected subcutaneously at the base of the tail with bovine type II collagen (200 μg) admixed. The mice are boosted 21 days later in the same manner. For preventative administration, PO QD dosing is immediately started with BMS-986142 in EtOH: TPGS: PEG300 (5:5:90); for therapeutic administration, the start of dosing is delayed until the booster immunization on day 21. For BMS-986142 plus MTX preventative studies, mice receive vehicle; BMS-986142 at 4, 10, or 30 mg/kg; BMS-986142 at 4 mg/kg plus MTX 0.25 mg/kg; or MTX at 0.25 mg/kg daily. For BMS-986142 plus etanercept therapeutic studies, mice receive vehicle daily; BMS-986142 at 2, 4, or 25 mg/kg daily; BMS-986142 at 2 or 4 mg/kg daily plus etanercept at 15 mg/kg IP twice weekly (BIW); or etanercept at 15 mg/kg IP BIW. For BMS-986142 plus murine cytotoxic T lymphocyte-associated protein 4 immunoglobulins (CTLA-4-Ig) preventative studies, mice receive vehicle daily; BMS-986142 at 10 or 30 mg/kg daily; murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW; or BMS-986142 at 10 mg/kg daily plus murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW. Dosing proceeds from day 0 through study completion (36 days).