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    CGI1746
    CGI1746

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0646
    CAS #: 910232-84-7Purity ≥98%

    Description: CGI1746 (CGI-1746) is a reversible/non-covalent and highly selective small-molecule inhibitor of the Bruton's tyrosine kinase-Btk with potential anti-inflammatory activity. It inhibits BTK with an IC50 of 1.9 nM. CGI-1746 shows high in vivo antiinflammatory efficacy in an anti-collagen II antibody–induced arthritis (CAIA) model in mice.

    References: Nat Chem Biol. 2011 Jan;7(1):41-50.

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    Molecular Weight (MW)579.69
    FormulaC34H37N5O4
    CAS No.910232-84-7
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (172.5 mM)
    Water: <1 mg/mL
    Ethanol: 33 mg/mL warmed (56.9 mM) 
    Other infoChemical Name: 4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide
    InChi Key: JIFCFQDXHMUPGP-UHFFFAOYSA-N
    InChi Code: InChI=1S/C34H37N5O4/c1-22-27(7-6-8-28(22)37-31(40)23-9-13-25(14-10-23)34(2,3)4)29-21-38(5)33(42)30(36-29)35-26-15-11-24(12-16-26)32(41)39-17-19-43-20-18-39/h6-16,21H,17-20H2,1-5H3,(H,35,36)(H,37,40)
    SMILES Code: O=C(NC1=CC=CC(C(N=C2NC3=CC=C(C(N4CCOCC4)=O)C=C3)=CN(C)C2=O)=C1C)C5=CC=C(C(C)(C)C)C=C5
    SynonymsCGI-1746; CGI 1746; CGI1746; 


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    In Vitro

    In vitro activity: CGI1746 is specific for Btk, with ∼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 had 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.


    Kinase Assay: 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[1]. 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.


    Cell Assay: 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.

    In VivoCGI1746 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.
    Animal modelmouse models
    Formulation & Dosage100 mg/kg; s.c. administration
    ReferencesNat Chem Biol. 2011 Jan;7(1):41-50.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    CGI1746

    CGI1746 blocks BCR-mediated responses in primary human and murine B cells and is efficacious in prophylactic CIA. Nat Chem Biol. 2011 Jan;7(1):41-50.

    CGI1746

    CGI1746 blocks FcγR-induced signaling and inflammatory cytokine production in murine macrophages. Nat Chem Biol. 2011 Jan;7(1):41-50.

    CGI1746

    Administration of CGI1746 inhibits the development of myeloid cell–dependent arthritis after transfer of arthritogenic antibodies and blocks inflammatory cytokine production. Nat Chem Biol. 2011 Jan;7(1):41-50.


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