生物活性

• 描述Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that plays a critical role in development, differentiation and proliferation of B-lineage cells. CGI-1746 is an ATP-competitive small molecule inhibitor of BTK with IC₅₀ value of 1.9 nM. In vitro, CGI-1746 potently inhibited all three anti-IgM-induced phosphorylation events in both human and murine B cells with an average IC₅₀ value of 2.9 nM, and completely inhibited the proliferation of CD27⁺IgG⁺ B cells, anti-IgM-induced murine and human B cell, with IC₅₀ values of 112 nM, 134 nM and 42 nM, respectively. However, CGI1746 had no effect on anti-CD3 and anti-CD28 induced T cell proliferation. CGI1746 could also inhibit the growth of human myeloma cell line APR1 and OCI-MY5 with IC₅₀ value of 10 μM. CGI1746 decreases cytokine levels within joints and ameliorates disease in myeloid- and FcgR-dependent autoantibody-induced arthritis. In vivo, administration of 100 mg/kg twice-daily with CGI-1746 for 4 weeks significantly inhibited overall clinical arthritis scores, and reduced anti-collagen II titers. CCGI-1746 suppressed TNFα, IL-1β, IL-6, MCP1 and MIP-1α production in the passive anti-collagen II antibody induced arthritis (CAIA) model. Treatment with CGI-1746 at the dose of 200 mg/kg twice a week for 30 days can inhibit the growth of human OCI-MY5 xenografts in NSG mice.

• 动物研究
  剂量	Mice: 100 mg/kg[2] (s.c.), 200 mg/kg[3] (s.c.)
  给药途径	s.c.