Novel Approaches for the Treatment of Inflammatory Diseases: Inhibitors of NF-KB and AP-1

The transcription factors (TF's) AP-I and NF-KB play a critical role in the regulation of several proinflammatory cytokines and related proteins and have thus been implicated in a number of immunoinflammatory and proliferative diseases. Recently, a great deal of work has been done to elucidate the regulatory pathways involved in the activation of NF-KB and AP-I. In addition, several antiarthritic drugs have been shown to block the activation of these transcription factors. These observations have led to drug discovery efforts aimed toward selectively modulating these targets. A variety of compounds have been shown to block these TF' s, however none has shown enough selectivity to warrant further clinical development. Recently, two new series of compounds were identified that block the activation of both NF-KB and AP-1 selectively in T-cells. Subsequently, they were shown to be active in several animal models of inflammation and immunosuppression. Current work is focused on identifying orally-active analogs to be used in the treatment of chronic diseases associated with an overproduction of NF-KB and AP- I.