Intracellular signal pathways: potential for therapies

Abstract

Drawbacks to current therapies for rheumatoid arthritis and the high cost of many of these drugs have lead to the investigation of novel approaches for treatment of this disease. One such tactic is the targeting of proteins involved in intracellular signal transduction. Inhibitors of p38 kinase have largely failed in clinical trials, due to both lack of efficacy and adverse events. The degree of adverse events may reflect off-target effects or, conversely, may be a mechanism-related event subsequent to successful inhibition of p38. Drugs targeting Janus kinases or spleen tyrosine kinase have shown greater success in clinical trials. A thorough analysis of specificity, as well as publication of both positive and negative results, must be the goal of continuing trials of these and other inhibitors of signal transduction molecules. The success of many clinical trials in this novel class of drugs provides optimism that more cost-effective and improved therapies will soon be available.

Figure 1

Schematic of intracellular signaling cascades. Cellular exposure to cytokines, chemokines, growth factors, pathogen-associated molecular patterns or antigens, endogenous danger signals, or stressors such as ultraviolet rays or absence of growth factors results in receptor ligation. Subsequent initiation of signaling cascades leads to altered expression patterns of genes involved in inflammation, degradation of extracellular matrix, apoptosis, and other cellular processes important in mounting an appropriate response to the stimuli. ASK—apoptosis signal-regulating kinase; ATF—activating transcription factor; ERK—extracellular signal-regulated kinase; IκB—inhibitor of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); IKK—IκB kinase; JAK—Janus tyrosine kinase; JNK—c-Jun N-terminal kinase; MAP-KAP— mitogen-activated protein kinase (MAPK) activated protein; MEK—MAPK/ERK kinase; MEKK—MAPK kinase kinase/MEK kinase; MLK—mixed lineage kinase; MKK—MAPK kinase; STAT—signal transducer and activator of transcription; Syk—spleen tyrosine kinase; TAK—transforming growth factor-β–associated kinase.