Charles J Malemud
Case Western Reserve University School of Medicine, USA
Title: How do Janus Kinase (JAK) inhibitors really work
Biography
Biography: Charles J Malemud
Abstract
The Janus Kinase/Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathway plays a prominent role in several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, psoriasis/psoriatic arthritis, and, inflammatory bowel disease. Thus, the continuous activation of JAK-STAT signaling mediated by the substantially elevated levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL-17, IL-12/IL-23 and interferon-γ, to name just a few in these diseases, disrupts many of the downstream cellular events regulated by JAK-STAT signaling. This often results in the aberrant survival of immune cells and accessory cells thus perpetuating chronic inflammation. The extent to which JAK-STAT signaling is involved in these autoimmune diseases led to the pre-clinical development and clinical trials evaluation of JAK small molecule inhibitors (SMIs), now referred to as “Jakinibs.” These include tofacitinib, ruxolitinib, and baricitinib which were FDA-approved for the medical management of RA, psoriasis and myeloproliferative disease. In a pre-clinical analysis, tofacitinib demonstrated a relative selectivity for JAK1/JAK3 compared to JAK1/JAK2. At the cellular level, ruxolitinib, a JAK1/JAK2- selective SMI was shown to reduce the plasma levels of IL-6 and CD-40 as well as the phosphorylation of STAT3 ex vivo using blood cells from RA patients. Conversely, in cell-free assays, baracitinib is relatively selective for JAK1/JAK2 (IC50=5.9/5.7nM, respectively) compared to JAK3 and Tyk2 and exhibits no inhibitory activity towards either the tyrosine-protein kinase Met or checkpoint kinase-2. Baracitinib was also shown to inhibit IL-6-stimulated or IL-23-stimulated phosphorylation of STAT3 as well as the downstream synthesis of the chemokine, monocyte chemoattractant protein-1. At present, studies are being conducted by our research group to determine the extent to which tofacitinib inhibits matrix metalloproteinase gene expression by cultured human chondrocytes.