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CGI-1746

CAS No. : 910232-84-7

MCE 站：CGI-1746

产品活性：CGI-1746 是一种有效的，高选择性的 Btk 抑制剂，IC₅₀ 值为 1.9 nM。

研究领域：Protein Tyrosine Kinase/RTK  |  Autophagy

作用靶点：Btk  |  Autophagy

In Vitro: CGI1746 is specific for Btk, with appr 1,000-fold selectivity over Tec ａnd Src family kinases. In an ATP-free competition binding assay, the dissociation constant for Btk is 1.5 nM. CGI1746 inhibits Btk activity in a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 inhibits both auto- ａnd transphosphorylation steps necessary for enzyme activation. CGI1746 completely inhibits anti-IgM-induced murine ａnd human B cell proliferation, with IC₅₀s of 134 nM ａnd 42 nM, respectively, but has no effect on anti-CD3- ａnd anti-CD28-induced T cell proliferation. CGI1746 potently inhibits the proliferation of CD27+IgG+ B cells isolated from the tonsils of four human donors with an average IC₅₀ of 112 nM. In macrophages, CGI1746 abolishes FcγRIII-induced TNFα, IL-1β ａnd IL-6 production. CGI1746 potently inhibits TNFα, IL-1β and, to a lesser extent, IL-6 (three- to eight-fold higher IC₅₀) production in human monocytes stimulated with immobilized or soluble immune complexes. CGI-1746 does not kill cells as well as the irreversible BTK inhibitors at the same drug concentration. CGI-1746 significantly reduces phosphorylation of both the BTK-A ａnd BTK-C proteins, indicating the auto-phosphorylation of the BTK-C isoform is inhibited in a manner similar to BTK-A. CGI-1746 does not kill LNCaP or DU145 prostate cancer cells at the same concentrations as Ibrutinib or AVL-292, but it demonstrates similar inhibition of BTK phosphorylation at tyrosine 233 in the SH3 domain.

In Vivo: CGI1746 abrogates B cell-dependent arthritis. CGI1746 treatment (100 mg/kg, s.c, twice-daily dosing) results in significant inhibition (97%) of overall clinical arthritis scores. CGI1746 treatment substantially reduces TNFα, IL-1β ａnd IL-6, as well as MCP1 ａnd MIP-1α on both the mRNA ａnd protein level in the passive anti-collagen II antibody-induced arthritis (CAIA) model. CGI1746 shows comparable efficacy to TNFα blockade ａnd significantly reduces clinical scores, as well as joint inflammation, in mice or rats with established arthritis.

相关产品：Bioactive Compound Library Plus  |  Immunology/Inflammation Compound Library  |  Kinase Inhibitor Library  |  Protein Tyrosine Kinase Compound Library  |  Autophagy Compound Library  |  Anti-Aging Compound Library  |  Pyroptosis Compound Library  |  Anti-Blood Cancer Compound Library  |  Ibrutinib-biotin  |  CG-806  |  LFM-A13  |  Ibrutinib deacryloylpiperidine  |  PCI 29732  |  Acalabrutinib D4

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