cc-292 and Arthritis--Rheumatoid

Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (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. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (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 a 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 valuable drug target for B-cell mediated disorders.

Topics: Acrylamides; Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; B-Lymphocytes; Double-Blind Method; Humans; Mice; Protein-Tyrosine Kinases; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction

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

By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC50=3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Arthritis, Rheumatoid; Dogs; Dose-Response Relationship, Drug; Humans; Molecular Conformation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship