Spleen Tyrosine Kinase (SYK) is an intracellular non-receptor cytoplasmic protein tyrosine kinase that serves as a key mediator of Fc receptor and B cell receptor signaling in inflammatory cells, including macrophages, neutrophils, mast cells, NK cells and B cells. The immunoreceptors, such as Fc receptors and B cell receptors, are important for both allergic and antibody-mediated immune diseases; therefore, inhibition of SYK that is positioned upstream in the signaling pathway may be more advantageous as a therapeutic target. An SYK inhibitor is likely to weaken both the initiation of the disease by blocking the B-cell receptor signaling, and the effector phase by blocking the FcγR signaling through neutrophils present in the synovial membrane. In addition to this, SYK inhibition has an additional benefit of inhibiting osteoclast maturation, attenuating the bone erosion, joint destruction and osteopenia associated with rheumatoid arthritis (RA).
RA is often progressive and debilitating and affects nearly 2.1 million people in the United States. The current treatment options for RA have potentially significant shortcomings and side effects. At present, RA patient receives multiple drugs depending on the extent and aggressiveness of the disease. Most RA patients require some form of disease modifying anti-rheumatic drugs including methotrexate or TNF-α blocking agent such as Enbrel. Up to 30 percent of patients continue to be resistant to these approaches and even in those that respond. Also, a range of toxicities occurs, including gastrointestinal complications, kidney damage, opportunistic infections and increased incidence of lymphoma. As such, there is a need to develop safer and more effective therapeutic strategies for RA. In this aspect, SYK offers a target-based approach that will give a great effect on multiple functions. A small molecule inhibitor for SYK that has better oral bioavailability could serve as a better therapeutic alternative by reducing the cost of treatment and pain of injections.
SKI-O-703, orally available drug, showed not only selective and highly potent activity (single nM range) but desirable drug-like properties with good safety. It showed great efficacy in collagen-induced arthritis (CIA) murine model, in a mouse model for systemic lupus erythematosus, and in a mouse model for immune thrombocytopenic purpura. SKI-O-703 is in clinical phase 1 stage (MAD) in the US. The single ascending dose study in clinical phase 1 study shows desirable human PK with no outstanding adverse events. The phase 1 study will be completed in Q2, 2017.
Its proposed indications are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and immune thrombocytopenic purpura (ITP) and its other indications are atopic dermatitis, asthma, allergy, and hemolytic anemia.
SKI-O-703 for treatment of rheumatoid arthritis (RA)
The CIA rats were treated with SKI-O-703, fostamatinib (RT88), and tofacitinib (CP-690,550) by daily oral dosing for 21 days. SKI-O-703 showed greater efficacy than fostamatinib as measured by clinical score/paw volume or histopathology/histomorphometry. Although mechanism of SKI-O-703 (selective SYK inhibitor) is different from that of tofacitinib (pan-JAKs inhibitor), it showed comparable efficacy with tofacitinib.
SKI-O-703 for treatment of systemic lupus erythematosus (SLE)
MRL-1pr/1pr mice were used as the SLE model. Once daily oral dosing of SKI-O-703 effectively prevents the development of skin lesions in MRL-1pr/1pr mice. Also, SKI-O-703 treatment significantly reduces kidney enlargement and proteinuria level, suggesting that it prevents kidney damage and subsequently maintains normal kidney function.
SKI-O-703 for treatment of immune thrombocytopenic purpura (ITP)
SKI-O-592 (free base of SKI-O-703) shows significantly reduced phagocytosis caused by IgG-opsonized latex bead stimulation in RAW 264.7 macrophage cells. ITP was induced in mice by injecting anti-CD41 antibody. SKI-O-703 effectively ameliorate thrombocytopenia in mouse ITP model, suggesting that SYK inhibition effectively inhibits FcγR-mediated phagocytosis.