Novel drug discovery assay to identify inhibitors of NFkB signaling

鉴定 NFkB 信号传导抑制剂的新药发现试验

• 批准号: 7669696
• 负责人: Mark W Nowak
• 金额: $ 20.52万
• 依托单位: ENCODE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669696
• 关键词: Adverse effects; Affect; Alkynes; Amino Acids; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Atherosclerosis; Azides; BODIPY; Binding; Binding Sites; Biological; Biological Assay; C-terminal; Catalytic Domain; Cell Nucleus; Cell Survival; Cells; Chemistry; Chronic; Complex; Coupled; Crohn' s disease; Development; Disease; Drug Industry; Enzymes; Etanercept; Family; Fluorescence; Future; Gene Expression; Grant; Hot Spot; Immune; Immune system; Immunoprecipitation; Induction of Apoptosis; Inflammatory; Inflammatory Response; Label; Location; Measures; Mediating; Membrane Proteins; Molecular Conformation; Monitor; Monoclonal Antibodies; Movement; Mutagenesis; Normal Cell; Optics; Pathway interactions; Peptides; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Preclinical Drug Evaluation; Protein Kinase; Protein Kinase Inhibitors; Proteins; Reaction; Research; Rheumatoid Arthritis; Role; Screening procedure; Signal Transduction; Site; Small Business Innovation Research Grant; Specificity; Surface; TNF gene; Techniques; Technology; Testing; Therapeutic; Transfection; Tryptophan; Tumor Necrosis Factor Receptor; base; conserved helix-loop-helix ubiquitous kinase; cytokine; design; drug discovery; fluorophore; infliximab; inhibitor/antagonist; kinase inhibitor; macromolecule; mutant; novel; novel strategies; preclinical study; prevent; protein kinase inhibitor; protein protein interaction; public health relevance; research study; small molecule; small molecule libraries; tool; transcription factor

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.

描述（由申请人提供）：NF（B介导细胞因子TNF的大多数生物学作用（在免疫系统的稳态控制中起着至关重要的作用。当NF（B过度活跃时，它可能会引起诸如类风湿关节炎和Crohn病等炎症性疾病，并且可以通过超固有性的方法来降低TNF（nf）。抗TNF的单克隆抗体（（ENBREL和REMICADE）由于TNF的任何小分子抑制剂（已成功开发了受体。但是，阻断TNF的方法（刺激NF（B信号传导将受益于该途径的小分子药物抑制剂的发展）。 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. 发现NEMO/IKK选择性抑制剂（可以通过使用化合物筛选测定法来促进结合，无论是用于主要筛查和设计为抑制剂设计的化合物的次级筛选。通常，通常很少有用于蛋白质相互作用的药物筛选。蛋白质相互作用的药物bio不需要开发的蛋白质与其他蛋白质相互作用。编码BIO建议适应我们的技术来测量蛋白质 - 蛋白质相互作用，以鉴定I（B激酶（ikk（IKK）（ikk（）），tnf（/nf（b信号传导））的新型小分子变构抑制剂。 公共卫生相关性：TNF（/NF（B信号传导在炎症性疾病中起关键作用），例如关节炎，动脉粥样硬化和克罗恩病。因此，药物阻止TNF（/NF（B信号传导）（B信号传导可能具有多种治疗作用，具有多种治疗作用，是抗炎性药物的抗炎性药物。 NF（B信号传导可以作为抗炎药开发。 但是，没有选择抑制Nemo和IKK之间相互作用的筛选分析。编码BIO建议开发一种药物筛查测定法，可用于鉴定这种蛋白质相互作用抑制剂。