Research Project
7669696
DESCRIPTION (provided by applicant): NF(B mediates most of the biological effects of the cytokine TNF( which plays a critical role in the homeostatic control of the immune system. When NF(B becomes overly active, it can cause inflammatory disorders such as rheumatoid arthritis and Crohn's disease. Presently, one of the only ways to reduce hyper-stimulation of the TNF(/NF(B pathway is through the use of monoclonal antibodies against TNF( (Enbrel and Remicade) since no small molecule inhibitors of the TNF( receptor have been successfully developed. However, approaches to block TNF( stimulation of NF(B signaling would benefit from the development of small molecule drug inhibitors of this pathway. A key factor controlling the actions of NF(B and mediating the effects of TNF( is I(B kinase (IKK). IKK activity is modulated by an allosteric activator, NEMO. Thus, small molecule inhibitors of the NEMO/IKK( interaction will likely block TNF( stimulation of NF(B signaling and might be useful as anti-inflammatory drugs. Discovery of selective inhibitors of NEMO/IKK( binding could be facilitated by the use of compound screening assays, both for primary screening as well as a secondary screen for compounds designed as inhibitors. Generally, there are few assays available for drug screening for protein-protein interactions. Encode Bio has developed an optical technology which can be employed to measure protein-protein interactions without some of the drawbacks of other assays. Encode Bio proposes to adapt our technology to measure protein-protein interactions to be able to identify novel small molecule allosteric inhibitors of I(B kinase (IKK() which block TNF(/NF(B signaling. PUBLIC HEALTH RELEVANCE: Abnormalities in TNF(/NF(B signaling play critical roles in inflammatory diseases such as arthritis, atherosclerosis and Crohn's disease. As a consequence, drugs blocking TNF(/NF(B signaling could have a number of therapeutic actions as anti-inflammatory agents. Specifically, small molecule drugs that block the binding interaction of NEMO to IKK inhibit NF(B signaling could be developed as anti-inflammatory drugs. However, there are no screening assays that select for inhibitors of the interaction between NEMO and IKK. Encode Bio proposes to develop a drug screening assay which can be employed to identify such protein- protein interaction inhibitors.
