Rapid Kinase Profiling with Luminescent Reporters

使用发光报告基因快速分析激酶

• 批准号: 8124548
• 负责人: REENA ZUTSHI
• 金额: $ 91.79万
• 依托单位: LUCEOME BIOTECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124548
• 关键词: ATP phosphohydrolase; Active Sites; Adverse effects; Architecture; Area; Binding; Binding Sites; Biological Assay; Cardiovascular Diseases; Cell Proliferation; Cells; Clinic; Clinical Trials; Collection; Communities; Complex; Dasatinib; Diabetes Mellitus; Disease; Drug Design; Early identification; Enzymes; Event; Failure; Family; Fingerprint; Goals; Gray unit of radiation dose; Human Genome; Individual; Inflammation; Lead; Link; Lipids; Luciferases; Luminescent Measurements; Malignant Neoplasms; Market Research; Marketing; Mediating; Mediator of activation protein; Metabolic Diseases; Methods; Neoplasm Metastasis; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphorylation; Phosphotransferases; Protein Kinase; Protein Tyrosine Kinase; Provider; Reporter; Research Personnel; Resources; Scaffolding Protein; Screening procedure; Services; Signal Transduction; Signal Transduction Pathway; Specificity; Staging; Staurosporine; Technology; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Validation; Work; base; cost; cross reactivity; drug candidate; drug development; drug discovery; inhibitor/antagonist; kinase inhibitor; luminescence; meetings; mutant; neoplastic cell; phase 1 study; pre-clinical; small molecule; success; therapeutic target

DESCRIPTION (provided by applicant): Approximately 518 kinases are encoded by the human genome and serve as critical mediators of signal transduction brought about by a phosphorylation event. Many kinases are known to be involved in diabetes, inflammation, cardiovascular diseases, tumor cell proliferation and metastasis and are therefore validated targets for therapeutic intervention. Currently there are 10 marketed kinase drugs, another 80 inhibitors are in clinical trials and many more are being evaluated in the preclinical stage. The kinases share a relatively similar architecture at the active-site (ATP-binding domain), making selectivity an issue in drug discovery and development. A promiscuous or 'dirty' drug, which binds to many kinases, is expected to give rise to unwanted adverse-effects. At the same time, in some cases, inhibiting multiple targets, like kinases, selectively in a signal transduction pathway might be a desired strategy for treating a disease. Profiling drug candidates against a large panel of kinases can therefore not only aid in anticipating toxicity profiles, but also help in identifying new targets for old compounds. In this Phase II application, we will develop our split-luciferase based luminescent assays for kinome-wide profiling. Currently due to the high costs of profiling against kinases, selectivity profiles are typically obtained later in drug development to verify the lead compound's specificity. In addition, many researchers are shut out on a routine basis. Our goal is to make these profiling assays affordable, so that compound profiling can be done earlier leading to early identification of failures and resulting in many more opportunities for success. PUBLIC HEALTH RELEVANCE: Kinases are important mediators of signal transduction pathways and their activity inside cells is tightly regulated. Dysregulation of kinases has been implicated in many diseases, validating them as therapeutic targets. The challenge in designing drugs against kinases comes from their cross-reactivity, which arises due to similar architecture of many kinases at the ATP-binding site. Screening compounds against a large number of kinases can help develop a selectivity fingerprint, which can be used to make important decisions for advancing a compound into the clinic. The purpose of our application is to develop low-cost, sensitive, luminescence based kinase assays for drug discovery.

描述（由申请人提供）：大约518个激酶由人类基因组编码，并用作由磷酸化事件带来的信号转导的关键介体。已知许多激酶都参与糖尿病，炎症，心血管疾病，肿瘤细胞增殖和转移，因此受到治疗干预的验证靶标。目前，有10种销售的激酶药物，还有80种抑制剂正在临床试验中，并且在临床前阶段正在评估更多抑制剂。激酶在活动地点（ATP结合域）上具有相对相似的体系结构，使选择性成为药物发现和开发中的问题。与许多激酶结合的混杂或“脏”药物有望产生不必要的不​​良影响。同时，在某些情况下，在信号转导途径中有选择地抑制多个靶标，例如激酶，可能是治疗疾病的所需策略。因此，针对大量激酶的候选药物进行分析不仅可以帮助预测毒性概况，还可以帮助确定旧化合物的新靶标。在此II阶段应用中，我们将开发基于分裂的葡萄酸酶的发光测定，用于范围内的酸性分析。目前，由于针对激酶的分析成本很高，通常在药物开发中获得选择性概况，以验证铅化合物的特异性。此外，许多研究人员常规被关闭。我们的目标是使这些分析测定能够负担得起，以便可以尽早完成复合分析，从而尽早确定失败并带来更多成功的机会。 公共卫生相关性：激酶是信号转导途径的重要介质，其在细胞内部的活性受到严格调节。激酶的失调与许多疾病有关，将其视为治疗靶点。针对激酶设计药物的挑战来自它们的交叉反应性，这是由于ATP结合部位的许多激酶的类似结构引起的。针对大量激酶的筛选化合物可以帮助开发选择性指纹，可以用来做出重要的决策，以将化合物推进诊所。我们应用的目的是开发低成本，灵敏，基于发光的激酶测定以进行药物发现。