pci-32765 and Lupus-Erythematosus--Systemic

Systemic lupus erythematosus (SLE) is a disabling and deadly disease. Development of novel therapies for SLE has historically been limited by incomplete understanding of immune dysregulation. Recent advances in lupus pathogenesis, however, have led to the adoption or development of new therapeutics, including the first Food and Drug Administration-approved drug in 50 years.. Multiple cytokines (interferon, B lymphocyte stimulator, IL-6, and IL-17), signaling pathways (Bruton's Tyrosine Kinase, Janus kinase/signal transducer and activator of transcription), and immune cells are dysregulated in SLE. In this review, we cover seminal discoveries that demonstrate how this dysregulation is integral to SLE pathogenesis and the novel therapeutics currently under development or in clinical trials. In addition, early work suggests metabolic derangements are another target for disease modification. Finally, molecular profiling has led to improved patient stratification in the heterogeneous SLE population, which may improve clinical trial outcomes and therapeutic selection.. Recent advances in the treatment of SLE have directly resulted from improved understanding of this complicated disease. Rheumatologists may have a variety of novel agents and more precise targeting of select lupus populations in the coming years.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B-Cell Activating Factor; Cyclic S-Oxides; Cytokines; Drug Approval; Drug Discovery; Humans; Immunologic Factors; Immunosuppressive Agents; Interferon-alpha; Interleukin-17; Interleukin-6; Isoquinolines; Janus Kinases; Lupus Erythematosus, Systemic; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recombinant Fusion Proteins; Rituximab; Signal Transduction; STAT Transcription Factors

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Drug Discovery; Humans; Indoles; Inhibitory Concentration 50; Lupus Erythematosus, Systemic; Macaca fascicularis; Mice; Piperidines; Protein Kinase Inhibitors

Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Dogs; Drug Discovery; Humans; Lupus Erythematosus, Systemic; Madin Darby Canine Kidney Cells; Models, Molecular; Molecular Structure; Piperazines; Protein Kinase Inhibitors; Pyridones; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley

On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-κB activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Autoimmunity; B-Lymphocytes; Cell Lineage; Gene Expression; Germinal Center; Lupus Erythematosus, Systemic; Lymphocyte Activation; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Piperidines; Plasma Cells; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.. B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.. In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.. These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Autoantibodies; Autoimmunity; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphocytes; Male; Mice, Congenic; Mice, Inbred C57BL; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Splenomegaly; Treatment Outcome