Targeting signaling pathways with small molecules to treat autoimmune disorders

Abstract

Chronic activation of immune responses, mediated by inflammatory mediators and involving different effector cells of the innate and acquired immune system characterizes autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and septic shock syndrome. MAPKs are crucial intracellular mediators of inflammation. MAPK inhibitors are attractive anti-inflammatory drugs, because they are capable of reducing the synthesis of inflammation mediators at multiple levels and are effective in blocking proinflammatory cytokine signaling. Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway converts cytokine signals into genomic responses regulating proliferation and differentiation of the immune cells. JAK inhibitors are a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory and antiallergic properties. This review discusses the rationale behind current strategies of targeting MAPK and JAK/STAT signaling pathways, and the overall effects of signal transduction inhibitors in animal models of inflammatory disorders. Signal transduction inhibitors are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disorders.

An Astrocyte-Specific Proteomic Approach to Inflammatory Responses in Experimental Rat Glaucoma

“…The janus kinase (JAK)/STAT signaling, along with the NF-jB signaling, has received a growing attention as key regulators of cytokine-mediated inflammation 53,54 and promising targets for immunomodulation. 55 Various components of the JAK/STAT signaling pathway recently have been indicated in the glaucomatous human retina, 5 ocular hypertensive rat retina, 56 and optic nerve. 57 Our MS/MS data also included glia maturation factors that mediate inflammation in the central nervous system and exhibit up-regulation in neurodegenerative diseases, 58 and the macrophage migration inhibitory factor (MIF), which is expressed by retinal glia 59 and has an important amplifying role in cytokine-mediated inflammatory diseases.…”

An Update on Calcineurin Inhibitor–Free Regimens

“…45 The small molecule JAK3 inhibitor tofacitinib (originally named CP-690,550) has been used in patients with rheumatoid arthritis (RA) and other autoimmune diseases, and interest in its relevance to transplantation seemed inevitable. 46,47 One appealing characteristic of tofacitinib is its selective inhibition of T cell effector function with its preservation of tolerance-promoting CD4+ FOXP3+ T regulatory cells, an ideal combination for transplantation. 48 A phase I trial using JAK3 inhibition in renal allograft recipients came soon after success was demonstrated in mice and NHP transplant models.…”

Small molecules and antibodies for the treatment of psoriasis: a patent review (2010–2015)

“…Tyrosine kinases phosphorylate tyrosine residues and blocking their enzymatic activity has proved to be a successful strategy [24]. JAK1 is involved in the activation of IFN-³ , IL-6 and IL-10 receptors.…”