CGI1746 is a potent and highly selective small-molecule Btk inhibitor with IC50 of 1.9 nM.

BTK:1.9 nM

CGI1746治疗（100 mg/kg,s.c,每日两次给药）导致整体临床关节炎的显著抑制（97％）.在阳性抗胶原蛋白II抗体诱导的关节炎模型中,CGI1746处理显著降低TNFα,IL-1β和IL-6以及MCP1和MIP-1αmRNA和蛋白质水平.CGI1746在患有关节炎的小鼠和大鼠体内,CGI1746显示与TNFα阻断较好的效力,并明显降低其临床评分,同时减少关节炎症.

CGI1746有效抑制从四个捐赠人的扁桃体中分离出的CD27+IgG+ B细胞的增殖,平均IC50为112 nM。CGI1746完全抑制抗IgM诱导的小鼠和人B细胞增殖,IC50s分别为134 nM 和 42 nM,但对抗CD3和抗CD28诱导的T细胞增殖没有影响。CGI1746在巨噬细胞中,消除FcγRIII诱导的TNFα,IL-1β和IL-6产生。CGI1746有效抑制固定化或可溶性的免疫复合物刺激的人单核细胞中TNFα和 IL-1β的产生,并较小程度地抑制IL-6产生。CGI1746对Btk具有特异性,选择性比Tec和Src家族激酶高～1,000倍。

CGI-1746 is dissolved in DMSO. 5×103?DU145 cells or 104?LNCaP cells per well, grown on 96 well plates for 24h, are treated with 1 to 30?μM BTK inhibitors. Cells are fixed after 72h with 2.5% formaldehyde, and stained with Hoechst 33342. Control cells are treated with DMSO. Cell images are acquired using an IN Cell Analyzer 2200 high content imaging system, with a 20X objective. At least 9 fields are imaged per single well of each experiment. Cell numbers are determined and statistics performed using IN Cell Investigator 3.4 high content image analysis software. Each experiment is replicated 3 times, and data are presented as mean±SD. Results are considered significant if p < 0.05.