Conclusions The present study collectively suggests RO9021 is a selective, potent and orally bioavailable small molecule SYK kinase in hibitor, which could serve as a promising chemical lead for the design of clinical Perifosine SYK inhibitors and could complement the current arsenal of tools in development for treatment of inflammation related and autoimmune related disorders. Introduction Effective treatments of human autoimmune diseases, which are complex and heterogeneous by nature, re quire therapeutic perturbation or restoration of multiple redundant and distinct mechanisms, or a master regula tor of such pathways. In the case of rheumatoid arthritis pathogenesis, the critical role of the adaptive im mune response and proinflammatory cytokines has been unequivocally established by the efficacy of marketed biologics targeting tumor necrosis factor alpha, interleukin 6, CD20 and CD80 86.

However, their effi cacy are capped Inhibitors,Modulators,Libraries by limited efficacy, with 40% of patients never responding to treatments and only 20% of patients experiencing a major reduction in disease activity. There thus remains a tremendous unmet clinical need for more effective therapeutic strategies, with a goal of sustained remission for a greater number of patients with RA. Current therapeutic strategies pursued by the bio pharmaceutical industry include those that target the janus kinase mediated signaling pathway, lympho cyte migration using chemokine CCR1 antagonist, and B cells using either depleting antibodies that recognize common cell surface antigens, such as CD22 and CD19, or blocking antibodies to B cell survival factor such as B cell activating factor or a proliferation inducing ligand.

Although the pan JAK inhibi tor tofacitinib was recently approved by the US Food and Drug Inhibitors,Modulators,Libraries Administration Inhibitors,Modulators,Libraries for the treatment of RA, it is still not superior to the biologics in terms of efficacy and safety. For other autoimmune diseases that are in dire need of safer and or more effective therapies, the anti BAFF antibody belimumab, despite showing marginal ef ficacy in clinical trials, was approved for treatment of systemic lupus erythematous. Disappointingly, an other anti BAFF antibody also did not show adequate efficacy in a phase 3 RA trial. Whether an agent that neu tralizes both BAFF and APRIL will produce better re sults remains to be seen.

Other emerging approaches target key enzymes involved in mediating multiple signal transduction pathways. One such enzyme is the spleen tyrosine kinase, which is a master regulator in coupling activated immunoreceptors Inhibitors,Modulators,Libraries to Inhibitors,Modulators,Libraries the mobilization of downstream signal transduction cascades that affect diverse biological selleck screening library functions. One of the best characterized modules in the transmission of B cell receptor activating signals within B cells is the SYK Brutons tyrosine kinase axis, where BTK acts as an essential downstream effector of SYK in regula ting both the maturation and survival of the B cell lineage.