pci-32765 and Arthritis--Rheumatoid

The Tec family of non-receptor tyrosine kinases comprises five members. The cellular expression and function of these kinases has implicated them as potential drug targets for the treatment of both malignant and autoimmune diseases. Most attention has focused on inhibitors of BTK kinase with ibrutinib already approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Multiple BTK inhibitors are being developed for both oncology and autoimmune disease indications.. BTK inhibitors being evaluated in rheumatoid arthritis are considered. Both inhibitors which have progressed to early clinical development, and those demonstrating activity in rodent models of arthritis are reviewed. These include both reversible and irreversible inhibitors of the kinase, most of which target the cysteine-481 residue of BTK. The selectivity of these inhibitors for Tec family kinases is considered.. Developing inhibitors of any kinase to treat of rheumatoid arthritis has proved problematic with regard to both efficacy and selectivity. It is anticipated that the more selective BTK inhibitors may prove more useful in treating arthritis, with the use of reversible inhibitors possibly offering a better strategy. Chronic dosing may exacerbate the emergence of drug resistance, with resistant mutations already observed in ibrutinib-treated patients.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Drug Design; Drug Resistance; Drugs, Investigational; Humans; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Collagen; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Mice; Mice, Inbred DBA; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Structure-Activity Relationship

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

Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antitubercular Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Drug Design; Male; Mice; Mice, Inbred DBA; Molecular Structure; Mycobacterium tuberculosis; Protein Kinase Inhibitors; Tuberculosis

Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.

Topics: Agammaglobulinaemia Tyrosine Kinase; Arthritis, Rheumatoid; Crystallography, X-Ray; Humans; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinoxalines

The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms.. PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production.. PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED(50) of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC(50) = 8 nM). Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC(50) = 2.6, 0.5, 3.9 nM, respectively). Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD(2), TNF-α, IL-8 and MCP-1.. PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; B-Lymphocytes; Cell Proliferation; Female; Humans; Immune Complex Diseases; Macrophages; Mast Cells; Mice; Mice, Inbred BALB C; Monocytes; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Despite tremendous advances in the therapy of rheumatoid arthritis (RA), there remains interest in oral agents that may offer benefits that are similar to, or better than, those of biologic therapies. In their paper, Chang and colleagues demonstrate the effectiveness of a Bruton tyrosine kinase (Btk) inhibitor in two models of RA. Btk inhibition impacts several pathways affecting both B-cell and macrophage activation, making it a promising target in RA. However, other kinase inhibitors have failed to transition from animal models to human therapy, so it remains to be seen whether a Btk inhibitor will have a role in the RA treatment armamentarium.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Female; Humans; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenosine Triphosphate; Agammaglobulinaemia Tyrosine Kinase; Amino Acid Sequence; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Binding Sites; Disease Models, Animal; Drug Design; Molecular Sequence Data; Oligopeptides; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Rodentia; Structure-Activity Relationship