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：
8577260
负责人：
RAPHAEL KOPAN
金额：
$ 32.42万
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/8577260
关键词：
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 Heterozygote Homeostasis Homozygote Human Investigation Knock-in Mouse Libraries Ligand Binding Link 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 association study high throughput screening homologous recombination human disease in vivo insight interest member monomer new technology notch protein novel paralogous gene postnatal promoter public health relevance 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）：异常的 Notch 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 Notch 信号传导的药物。然而，对小鼠的研究预测这些药物会对多种器官系统产生毒性。在人体中已证实对胃肠道和皮肤有毒性，后者会导致非黑色素瘤皮肤癌的发病率升高。我们已经证明，除了增加癌症发病率之外，专门针对 Notch1 还会导致血管瘤在皮肤中；如果这种情况发生在人类身上，它将限制抗 Notch1 疗法在慢性疾病中的治疗潜力。最近，我们和我们的合作者报道，活性Notch分子的二聚化是一些靶基因激活的重要步骤，并且是Notch1在T细胞白血病（T-ALL）中致癌活性所必需的。 T-ALL对Notch二聚化的绝对依赖性提供了一种新的基于机制的治疗途径。然而，由于观察的新颖性以及缺乏能够区分二聚化依赖性和非二聚化依赖性靶标的工具，目前尚不清楚在Notch信号传导中针对这一方面的生物学后果。我们很幸运获得 ARRA 资金来开发一项新技术，该技术可以使用大肠杆菌 DNA 腺嘌呤甲基转移酶 (DAM) 的互补片段来询问不同多成员复合物的靶标选择。它是识别Notch二聚化依赖性靶标的理想新方法。在本申请中，我们建议通过定义治疗窗口（体内不良反应的范围）、识别二聚化依赖性靶标（如果该窗口被证明太窄或药物发现太窄）来促进“二聚体破坏”疗法的药物开发工作。努力太困难）并利用我们的二聚体敏感测定和高通量筛选来识别药物先导化合物。