Novel drug discovery assay to identify inhibitors of NFkB signaling

说明(由申请人提供)：核因子(B)介导细胞因子肿瘤坏死因子(在免疫系统的动态平衡控制中起关键作用)的大部分生物学效应。当核因子(B)变得过度活跃时，会引起类风湿性关节炎和克罗恩病等炎症性疾病。目前，由于尚未成功开发出肿瘤坏死因子受体的小分子抑制剂，目前唯一能减少肿瘤坏死因子受体B通路过度刺激的方法之一是使用抗肿瘤坏死因子受体的单抗(Enbrel和Remicade)。然而，阻断对NF(B)信号的刺激的方法将受益于这一途径的小分子药物抑制剂的开发。 控制核因子(B)的作用和介导肿瘤坏死因子(TNF)作用的一个关键因素是I(B激酶(Ikk)。IKK活性受变构激活剂NEMO的调节。因此，NEMO/IKK(相互作用)的小分子抑制剂可能会阻断对NF(B)信号的刺激，并可能用作抗炎药物。 发现NEMO/IKK的选择性抑制剂(结合可通过使用化合物筛选试验来促进，既可用于初步筛选，也可用于作为抑制剂的化合物的二次筛选。一般说来，用于蛋白质-蛋白质相互作用的药物筛选的方法很少。Encode Bio已经开发出一种光学技术，可以用来测量蛋白质之间的相互作用，而不会像其他分析方法那样存在一些缺点。Encode Bio建议采用我们的技术来测量蛋白质-蛋白质的相互作用，以便能够识别出新型的小分子I(B激酶)变构抑制剂(ikk())，它可以阻断TNF(/NF(B)信号。 公共卫生相关性：肿瘤坏死因子/核因子(B)信号异常在关节炎、动脉粥样硬化和克罗恩病等炎症性疾病中起关键作用。因此，阻断肿瘤坏死因子/核因子(B)信号转导通路的药物可作为抗炎药物发挥多种治疗作用。具体地说，阻断NEMO与IKK结合的小分子药物可抑制NF(B)信号转导，可作为抗炎药物开发。 然而，目前还没有筛选方法来筛选NEMO和IKK之间相互作用的抑制剂。Encode Bio建议开发一种药物筛选试验，可用于识别这种蛋白质-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.