Novel drug discovery assay to identify inhibitors of NFkB signaling

说明（申请人提供）：NF（B）介导细胞因子TNF（其在免疫系统的稳态控制中起关键作用）的大部分生物效应。当NF（B）变得过度活跃时，它可引起炎症性疾病，如类风湿性关节炎和克罗恩病。目前，减少TNF β/NF β B途径过度刺激的唯一方法之一是通过使用抗TNF β的单克隆抗体（Enbrel和Remicade），因为还没有成功开发出TNF β受体的小分子抑制剂。然而，阻断TNF刺激NF β B信号传导的方法将受益于该途径的小分子药物抑制剂的开发。 I（B激酶（IKK）是控制NF（B）作用和介导TNF（TNF）作用的关键因子。IKK活性由别构激活剂NEMO调节。因此，NEMO/IKK β相互作用的小分子抑制剂将可能阻断TNF β刺激NF β B信号传导，并且可能用作抗炎药物。 NEMO/IKK（结合）的选择性抑制剂的发现可以通过使用化合物筛选测定来促进，所述化合物筛选测定既用于初级筛选，也用于设计为抑制剂的化合物的次级筛选。一般来说，有几个测定可用于药物筛选蛋白质-蛋白质相互作用。Encode Bio开发了一种光学技术，可用于测量蛋白质-蛋白质相互作用，而没有其他分析的一些缺点。Encode Bio建议调整我们的技术来测量蛋白质-蛋白质相互作用，以便能够鉴定新型小分子I（B激酶（IKK）变构抑制剂，其阻断TNF（/NF（B）信号传导。 公共卫生相关性：TNF β/NF β B信号通路的异常在关节炎、动脉粥样硬化和克罗恩病等炎症性疾病中起重要作用。因此，阻断TNF α/NF β B信号传导的药物可以作为抗炎剂具有许多治疗作用。具体而言，阻断NEMO与IKK结合相互作用的小分子药物抑制NF（B）信号传导，可以开发为抗炎药物。 然而，没有筛选测定来选择NEMO和IKK之间相互作用的抑制剂。Encode Bio提出开发一种药物筛选测定法，可用于鉴定此类蛋白质-蛋白质相互作用抑制剂。

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.