Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma

描述（由申请人提供）：本项目旨在开发三种蛋白激酶，即EGFR、TBK 1和DDR2，作为非小细胞肺癌（NSCLC）的治疗靶点。 选择这些靶点是因为患者接受突变选择性治疗，但通常会产生耐药（EGFR），因为突变很常见，没有有效的靶向药物，但我们有一个很好的候选下游靶点（TBK 1代表突变型KRAS），或者因为存在新的基因组改变，为肺癌组织学，鳞状细胞癌，没有经过验证的目标（DDR2）。 我们的计划整合了分子和细胞药理学，化学，结构生物学和小鼠建模，其总体目标是开发在基于细胞和基因工程小鼠模型中具有活性的特定激酶抑制剂，具体目标如下。 - 总体目标1。使用药物化学和基于结构的药物设计开发有效的和可能的多药耐药EGFR，TBK 1和DDR2的选择性抑制剂。 核心A（化学）已经开发出有前途的先导化合物，以抑制嘧啶类药物耐药的EGFR（项目1），TBK 1（项目2）和DDR2（项目3）。 每个项目都将与核心A（化学）和B（结构）合作，根据细胞筛选和纯化激酶的结构分析优化化合物。 - 总体目标2。使用肺癌的细胞和动物治疗模型表征激酶抑制剂及其靶点。 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种激酶相关的肺癌基因工程小鼠模型。 - 总体目标3。采用合理的设计和基于细胞的方法来识别抑制剂耐药突变，并将此信息用于激酶抑制剂的设计和优化。 我们对EGFR抑制剂耐药性的洞察将用于设计新的抑制剂，克服所有三个靶点的耐药突变。

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.