BTK Inhibitors for Autoimmune Diseases

A series of additional BTK inhibitors is being screened in efficacy, pharmacokinetic (PK), and safety assays that are designed to identify compounds that potently inhibit BTK and exhibit kinase selectivity and pharmaceutical properties better suited for autoimmune diseases. Lead compounds show >2500-fold selectivity for BTK over other tyrosine kinases including EGFR and JAK-3.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, systemic disorder classified as an autoimmune disease. Symptoms of RA manifest as inflammation in the joints (arthritis) and can quickly progress to involve painful swelling and deterioration of the surrounding tissues and organs. Thus, RA can be very debilitating as patients may experience substantial loss of function and mobility in the hands, wrists, and feet. Though there is no known cure for RA, there are different types of treatments available to alleviate symptoms and modify disease progression. Unfortunately, many of the available therapies have significant side effects and long-term risks.

Autoimmune diseases such as RA are characterized by pathogenic autoantibody production (such as the presence of Rheumatoid Factor and antibodies to citrullinated peptides) as well as immune-complex mediated activation of Fc-gamma signaling pathways resulting in pro-inflammatory cytokine production of effector cells (macrophages, neutrophils, mast cells) leading to tissue destruction primarily in the joints. BTK is key component of BCR signaling in B cells and Fc-gamma signaling in myeloid cells. Therefore, inhibition of BTK activity is expected to reduce two major components of autoimmune diseases: the pathogenic autoantibody production by B cells and the pro-inflammatory cytokines produced by myeloid cells.