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). 01/2011; 7(1):41-50. DOI: 10.1038/nchembio.481
Source: PubMed


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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    ABSTRACT: Although expressed in several haematological lineages and involved in multiple different signalling pathways, Bruton tyrosine kinase (BTK) plays an indispensible role in B cells in signalling from the B cell receptor (BCR) for antigen. Many B cell malignancies remain dependent on constitutive BCR signalling, making BTK a functional therapeutic target. Several BTK inhibitors (BTKi) with different kinomes and modes of action are being assessed clinically. This review documents the efficacy and toxicity of BTKi in chronic lymphocytic leukaemia (CLL). Clinically, the furthest in development is ibrutinib (trade name, Imbruvica), an irreversible BTKi, which has shown spectacular preliminary efficacy, with rapid reductions in lymph nodes accompanied by peripheral blood lymphocytosis. The lymphocytosis resolves slowly and most patients do not enter a complete remission. Nevertheless, it is possible to maintain many CLL patients, even those with adverse cytogenetic features, on drug for many months with minimal toxicities, thus potentially transforming the therapeutic paradigms for CLL. The efficacy, lack of toxicity and oral administration of BTKi will ensure their adoption in a wide range of B cell malignancies. An outstanding challenge is to incorporate BTKi with other precision medicines in a mechanism-based manner in order to dispense with conventional chemotherapy.
    British Journal of Haematology 04/2014; 166(1). DOI:10.1111/bjh.12895 · 4.71 Impact Factor
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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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    ABSTRACT: Small molecule inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clinical outcomes in cancer patients. Recently Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in early clinical trials and has progressed into phase III trials. However, additional research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclinical and clinical development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292, and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.
    Journal of Hematology & Oncology 08/2013; 6(1):59. DOI:10.1186/1756-8722-6-59 · 4.81 Impact Factor
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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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    ABSTRACT: Targeted therapies that suppress BCR signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Btk plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. CC-292 is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with an innovative trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a compelling drug target.
    Journal of Pharmacology and Experimental Therapeutics 05/2013; 346(2). DOI:10.1124/jpet.113.203489 · 3.97 Impact Factor
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