Spleen Tyrosine Kinase (SYK) is an intracellular tyrosine kinase involved in receptor signaling, respectively, and is frequently activated during the course of inflammatory autoimmune diseases. It is mostly expressed in B lymphocytes, mast cells, macrophages, and neutrophils, and at lower levels in some epithelial cells, fibroblasts, and endothelial cells. SYK is not expressed in T-cells.
SYK is a receptor-coupled kinase, acting immediately downstream of hematopoietic receptors. It is activated via Fc receptor (FcR). The binding of SYK to FcR activates the downstream signaling events that eventually result in cytokine production and inflammation. These mediators cause inflammation and damage to tissue, cartilage, and at a later stage, bone. As most of these SYK -associated receptors are localized in immunological cells, SYK is a key component to the activation of immune cells that play critical roles in the pathogenesis of RA and other autoimmune diseases.
SYK plays a key role in the onset and progression of RA and other autoimmune diseases. Ample evidence indicates that autoimmunity results from over-activation of the SYK kinase, in particular in RA. Most notably, increased levels of activated (phosphorylated) SYK are found in the synovial fluid of RA patients. Furthermore, SYK is also crucial for transmitting signals in osteoclasts, the bone resorbing cells, required for their maturation and activation.
Since the expression of SYK is limited to cells of the immune system, and since it has multifunctional roles in the progression of RA, a SYK inhibitor could be acting at various levels of the disease, from the inflammation to the damage to the bone and tissue, modifying the course of the disease and leading to remission.
Dynamix is developing its highly selective Type II kinase inhibitor for SYK, DNX-2000, in collaboration with Teva Pharmaceuticals, for the treatment of multiple autoimmune disorders.