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

基本信息

批准号：
8490596
负责人：
MATTHEW L. MEYERSON
金额：
$ 150.64万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
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/8490596
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

项目摘要

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）：该程序旨在开发三种蛋白激酶，抗抑制剂EGFR，TBK1和DDR2，作为非小细胞肺癌（NSCLC）的治疗靶标。 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). 我们的程序将分子和细胞药理学，化学，结构生物学和小鼠建模集成到通过以下特定目的开发在基于细胞和遗传学的小鼠模型中活跃的特定激酶抑制剂的总体目的。 - 以后的目标1。使用基于药物化学和基于结构的药物设计，在可能的情况下发展有效的突变体选择性抑制剂。 Core A（化学）已开发出有希望的铅化合物来抑制吡啶胺抑制剂耐药EGFR（项目1），TBK1（项目2）和DDR2（项目3）。每个项目都将与核A（化学）和B（结构）合作，以基于细胞筛选和纯化激酶的结构分析来优化化合物。 - 与AIM 2。使用肺癌的细胞和动物治疗模型在药理学上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，继续生成和研究与每个激酶相关的肺癌的基因工程小鼠模型。 - 所有目标3。采用理性设计和基于细胞的方法来识别抑制剂耐药性突变，并在激酶抑制剂设计和优化中使用这些信息。我们对抗EGFR抑制剂的抗性的洞察力将用于设计新的抑制剂，以克服所有三个靶标的耐药性突变。