Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma

非小细胞肺癌的蛋白激酶治疗靶点

• 批准号: 8660037
• 负责人: MATTHEW L. MEYERSON
• 金额: $ 169.53万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660037
• 关键词: Advanced Development; Animal Model; Animals; Biochemical; Biological; Cancer Etiology; Cancer Histology; Cancer Model; Cancer cell line; Cell Survival; Cells; Cellular Assay; Cessation of life; Chemistry; Chronic; Complex; Crystallization; DDR2 gene; Development; Drug Design; Drug resistance; Enzyme Kinetics; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; FDA approved; Generations; Genes; Genetically Engineered Mouse; Genomics; Goals; KRAS2 gene; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Molecular Target; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Patients; Pharmaceutical Chemistry; Pharmacology; Phosphotransferases; Protein Analysis; Protein Kinase; Protein Kinase Inhibitors; Proteins; Pyrimidine; Research Personnel; Resistance; Resistance development; Roentgen Rays; Squamous Cell; Squamous cell carcinoma; Structure; TBK1 gene; Testing; Therapeutic; Therapeutic Studies; Treatment Efficacy; Tumor-Derived; United States; Validation; Work; Xenograft procedure; base; cancer cell; cancer type; design; discoidin domain receptor 2; functional genomics; in vivo; inhibitor/antagonist; insight; killings; kinase inhibitor; mouse model; mutant; programs; protein kinase inhibitor; resistance mechanism; resistance mutation; screening; small molecule; structural biology; therapeutic target; tumor

DESCRIPTION (provided by applicant): This Program aims to develop three protein kinases, inhibitor-resistant EGFR, TBK1, and DDR2, as therapeutic targets in non-small cell lung cancer (NSCLC). These targets were chosen because patients are treated with mutation-selective therapy but typically develop resistance (EGFR), because the mutation is common and there is no effective targeted agent but we have an excellent candidate downstream target (TBK1 for mutant KRAS), or because there is a new genomic alteration providing an opportunity for a lung cancer histology, squamous cell carcinoma, for which there is no validated target (DDR2). Our program integrates molecular and cellular pharmacology, chemistry, structural biology and mouse modeling with the overarching aim of developing specific kinase inhibitors that are active in cell-based and genetically engineered mouse models, through the following specific aims. -Overall aim 1. Develop potent and where possible mutant-selective inhibitors of inhibitor-resistant EGFR, TBK1, and DDR2 using medicinal chemistry and structure-based drug design. Core A (Chemistry) has developed promising lead compounds to inhibit pyrimidine inhibitor-resistant EGFR (Project 1), TBK1 (Project 2), and DDR2 (Project 3). Each project will collaborate with Cores A (Chemistry) and B (Structure) to optimize compounds based on cellular screens and on structural analysis of purified kinases. -Overall aim 2. Characterize kinase inhibitors and their targets pharmacologically using cellular and animal therapeutic models of lung cancer. Investigators from each Project will work with Core C (Animal) to continue generating and studying genetically engineered mouse models of lung cancer relevant to each kinase. -Overall aim 3. Employ rational design and cell-based approaches to identify inhibitor resistance mutations and to use this information in kinase inhibitor design and optimization. Our insight into resistance to EGFR inhibitors will be used to design new inhibitors that overcome drug resistance mutations for all three targets.

描述(由申请人提供)：该计划旨在开发三种蛋白激酶，即耐药EGFR、TBK1和DDR2，作为非小细胞肺癌(NSCLC)的治疗靶点。之所以选择这些靶点，是因为患者接受了突变选择性治疗，但通常会产生耐药性(EGFR)，因为突变很常见，没有有效的靶向制剂，但我们有一个很好的候选下游靶点(突变KRAS的TBK1)，或者因为有一种新的基因组变化为肺癌组织学提供了机会，即鳞状细胞癌，对于它来说，没有有效的靶点(DDR2)。我们的计划整合了分子和细胞药理学、化学、结构生物学和小鼠模型，主要目标是通过以下具体目标开发在细胞和基因工程小鼠模型中活跃的特定激酶抑制剂。 -总体目标1.利用药物化学和基于结构的药物设计，开发具有抑制剂抗性的EGFR、TBK1和DDR2的有效且在可能的情况下具有突变选择性的抑制剂。核心A(化学)已经开发出有前景的先导化合物来抑制对嘧啶抑制剂具有抗药性的EGFR(项目1)、TBK1(项目2)和DDR2(项目3)。每个项目都将与核心A(化学)和核心B(结构)合作，基于细胞筛选和对纯化的激酶的结构分析来优化化合物。 -总体目标2.利用肺癌的细胞和动物治疗模型，从药理学的角度表征激酶抑制剂及其靶标。每个项目的研究人员将与Core C(动物)合作，继续产生和研究与每个激酶相关的肺癌基因工程小鼠模型。 -总体目标3.使用合理的设计和基于细胞的方法来识别抑制剂耐药突变，并在激酶抑制剂的设计和优化中使用这些信息。我们对EGFR抑制剂耐药性的洞察将被用于设计新的抑制剂，以克服所有三个靶点的耐药性突变。