ASSESSING THE THERAPEUTIC WINDOW FOR FUTURE ANTI-NOTCH DIMERIZATION AGENTS

评估未来抗缺口二聚剂的治疗窗口

基本信息

批准号：
9064095
负责人：
RAPHAEL KOPAN
金额：
$ 32.39万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064095
关键词：
Acute T Cell Leukemia Address Adenine Adult Advanced Development Adverse effects Affinity Alleles Award Binding Biological Biological Assay Categories Cell Line Cell Nucleus Chronic Disease Collaborations Complement Complex DNA DNA Binding DNA-Binding Proteins Data Dependence Development Dimerization Dominant-Negative Mutation Drug Industry Drug Targeting Embryonic Development Enhancers Ensure Epitopes Escherichia coli Funding Future Gene Targeting Genetic Transcription Head Health Heterozygote Homeostasis Homozygote Human Investigation Knock-in Knock-in Mouse Libraries Ligand Binding Link LoxP-flanked allele Malignant Neoplasms Methods Methyltransferase Mus Mutant Strains Mice Mutation Myocardium Neoplasms in Vascular Tissue Neurons Nucleic Acid Regulatory Sequences Oncogenes Oncogenic Pathology Pharmaceutical Preparations Phenotype Play Preclinical Drug Evaluation Proteins Reagent Receptor Signaling Reporter Reporting Role Signal Transduction Site Skin Skin Carcinoma Specificity Staging T-Cell Leukemia T-Lymphocyte Technology Testing Therapeutic Therapeutic Uses Tissues Toxic effect Transcript Transcriptional Activation Transgenic Organisms Validation base body system c-Myc Staining Method cell type combinatorial compound 30 design dimer drug development drug discovery embryonic stem cell gastrointestinal genome-wide analysis high throughput screening homologous recombination human disease in vivo insight interest member monomer new technology notch protein novel paralogous gene postnatal promoter small molecule small molecule libraries therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Aberrant Notch signals have been linked to cancer and other human diseases, which has motivated the pharmaceutical industry to develop agents inhibiting Notch signaling. However, studies in the mouse predicted that these agents would be toxic to various organ systems. Confirmed in humans are toxicities to the gastrointestinal track and skin, the latter leading to elevated rates of non-melanoma skin cancer. We have shown that targeting Notch1 specifically will result in vascular tumors in addition to increasing cancer rates in the skin; if this will occur in humans it will limit the therapeutic potential of anti-Notch1 therapies in a chronic disease setting. Recently, we and our collaborators reported that dimerization of active Notch molecules is an important step in the activation of some target genes and is required for the oncogenic activity of Notch1 in T-cell leukemia (T-ALL). The absolute dependence of T- ALL on Notch dimerization provides a novel mechanism-based therapeutic avenue. However, the biological consequences of targeting this aspect in Notch signaling are currently unknown due to novelty of the observation and the lack of tools that can differentiate dimerization-dependent from -independent targets. We were fortunate to be awarded ARRA funds to develop a new technology that can interrogate target selection by different multi-member complexes using complementing fragments of the E. coli DNA Adenine methyltransferase (DAM). It is an ideal novel method to identify Notch dimerization dependent targets. In this application we propose to facilitate drug development efforts for 'dimer-busting' therapeutics by defining the therapeutic window (the spectrum of untoward effects in vivo), by identifying dimerization dependent targets (should this window prove to be too narrow or the drug discovery efforts too difficult) and by utilizing our dimer-sensitive assay and high throughput screening to identify drug leads.

描述（由申请人提供）：异常凹槽信号与癌症和其他人类疾病有关，这促使制药行业开发抑制凹槽信号的药物。但是，小鼠中的研究预测，这些药物对各种器官系统有毒。在人类中确认是对胃肠道轨迹和皮肤的毒性，后者导致非黑色素瘤皮肤癌的发生率升高。我们已经表明，针对Notch1的靶向还会导致血管肿瘤除了癌症率提高。在皮肤中；如果在人类中发生这种情况，它将限制慢性疾病环境中抗Notch1疗法的治疗潜力。最近，我们和我们的合作者报告说，主动缺口分子的二聚化是某些靶基因激活的重要一步，对于T-Cell白血病（T-All）中Notch1的致癌活性是必需的。 T-全部对Notch二聚化的绝对依赖性提供了一种基于机制的新型治疗途径。但是，由于观察到的新颖性以及缺乏可以区分二聚化依赖性与非独立目标的工具，目前尚不清楚靶向Notch信号中这一方面的生物学后果。我们很幸运地获得了ARRA资金，以开发一种新技术，可以使用大肠杆菌DNA DNA腺嘌呤甲基转移酶（DAM）的互补片段通过不同的多成员复合物询问目标选择。这是一种理想的新方法，可以识别dotch二聚化依赖性目标。在此应用中，我们建议通过定义治疗窗口（体内效果的频谱）来促进药物开发的工作，以识别依赖性的靶标（如果该窗口过于狭窄或过于困难），并利用我们的Dimer-niger-spections sputs sputs sputise sputs senputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs insputs，则可以通过识别依赖性靶标进行识别。