N-[3-[4,5-Dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyrazinyl]-2-methylphenyl]-4-(tert-butyl)benzamide

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

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.

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.

CGI1746 is a potent, selective inhibitor of Bruton’s tyrosine kinase (BTK; IC₅₀ = 1.9 nM), a non-receptor tyrosine kinase that is important in B lymphocyte development. It blocks both auto-and trans-phosphorylation of BTK by occupying an SH3 binding pocket in the un-phosphorylated enzyme. CGI1746 prevents B-cell antigen receptor-mediated B lymphocyte proliferation and suppresses FCγRIII-induced TNFα, IL-1β, and IL-6 production in macrophages. It reduces cytokine levels within joints and ameliorates symptoms in a mouse model of autoantibody-induced arthritis.

CGI 1746 is a Bruton’s tyrosine kinase (Btk) inhibitor to be used in antitumor drugs.

Btk

Store at -20°C