Article

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis

Department of Discovery Biology, CGI Pharmaceuticals, Branford, Connecticut, USA.
Nature Chemical Biology (Impact Factor: 13.22). 01/2011; 7(1):41-50. DOI: 10.1038/nchembio.481
Source: PubMed

ABSTRACT Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

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    • "for BTK activation. CGI-1746 therefore has exquisite sensitivity for BTK (Di Paolo et al, 2011). Whether this molecule is now being developed for clinical use is not clear. "
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    • "CGI-560, a benzamide derivative, is a highly selective (>10 fold) but modestly potent small molecule inhibitor of BTK with an IC50 of 400 nM in enzymology assays [74]. Optimization of CGI-560 property by medicinal chemistry led to the discovery of another benzamide analogue (CGI-1746) with exquisite potency and unique BTK-inhibitory activity [74]. "
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    • "CC-292 demonstrated therapeutic efficacy in a mouse CIA model, with 85 and 95% inhibition of disease observed at doses of 10 mg/kg per day and 30 mg/kg per day, respectively. The reduced disease severity seen with CC-292 treatment recapitulates xid mice, which harbor an inactivating mutation in the Btk gene and have a reduced incidence and severity of CIA disease induction (Mangla et al., 2004), as well as previous studies using pharmacological inhibition of Btk to reduce disease activity in autoimmune models (Honigberg et al., 2010; Chang et al., 2011; Di Paolo et al., 2011; Liu et al., 2011a). In addition to a full phenotypic response, once daily, oral dosing of 10 mg/kg CC-292 resulted in 84% Btk inhibition verified by Btk occupancy analysis assayed 2 hours after dose administration. "
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