Developing Selective EphA2 Inhibitors for the treatment of Cancer

开发用于治疗癌症的选择性 EphA2 抑制剂

基本信息

批准号：
8429912
负责人：
NATHANAEL Schiander GRAY
金额：
$ 52.45万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-29 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429912
关键词：
A549 Address Alleles Antineoplastic Agents Biochemical Biological Biological Assay Biological Process Breast Cancer Patient Cancer cell line Cellular biology Chemicals Development Drug Design Drug Targeting Drug resistance Engineering Eph Family Receptors Epidermal Growth Factor Receptor Exhibits Family Genetic Engineering Genetically Engineered Mouse Genotype Glioblastoma Goals Gray unit of radiation dose Institution LRRK2 gene Laboratories Lead Ligands Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Molecular Abnormality Mus Mutation Names Oncogenic Ovary Pattern Formation Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Play Property Prostate Protein Kinase Inhibitors Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Reference Standards Regulation Resistance Resolution Signal Transduction Small Interfering RNA Specificity Structure System Testing Therapeutic Therapeutic Effect Tumor Cell Line Validation Xenograft procedure angiogenesis base cancer cell cancer therapy cancer type cellular engineering clinical care design drug discovery in vivo in vivo Model inhibitor/antagonist kinase inhibitor malignant breast neoplasm melanoma multidisciplinary mutant pre-clinical protein kinase inhibitor public health relevance research study structural biology success tool tumor

项目摘要

DESCRIPTION (provided by applicant): The dramatic anti-cancer activity of protein kinase inhibitors that target specific driver-mutations such as Bcr- Abl, EML4-ALK, mutant EGFR and V600E b-raf is revolutionizing cancer drug discovery. Emerging evidence suggests that abnormal EphA2 kinase activity plays a key role in many types of cancers, including breast, lung, ovary, prostate, glioblastoma, and melanoma as well as a general mechanism of drug resistance to inhibitors of various receptor tyrosine kinases. The Eph system is the largest tyrosine kinase family with 16 RTKs and 9 ligands and has been implicated in a vast array of biological functions ranging from pattern formation during early development to angiogenesis to de-regulation during tumor development. Pharmacological interrogation of the function of specific Eph kinases is currently impossible due to the lack of potent, selective and well- characterized inhibitors. Here we proposed to use a directed-medicinal chemistry approach to develop potent and selective inhibitors of EphA2 and to use these compounds to validate EphA2 as a potential target using cellular and murine models of melanoma and lung cancer. We have identified type I and type II ATP- competitive inhibitors exemplified by 9-14 that exhibit potent activity against EphA2 and other Eph kinases, and here we propose further optimization of potency, selectivity, and pharmacological properties using structure- guided medicinal chemistry (Aims 1&2). The existing and newly generated compounds will be broadly profiled for their antiproliferative activities and, in conjunction with engineered EphA2 drug-resistant alleles will be used to validate EphA2 as a potential target using cellular and murine models of melanoma and lung cancer (Aim 3). Our laboratory has had considerable success in developing first-in-class inhibitors of ALK, Mps1, Erk5, mTor, LRRK2, FGFRs, JNKs, and the T790M mutant form of EGFR and in using these compounds to validate new cancer targets. To accomplish these goals we have assembled a world-class, multidisciplinary team that integrates medicinal chemistry (Gray), structural biology (Knapp), Eph-signaling (Chen), cancer cell biology (Benes, Chen, Tsao), tumor models (Wong, Chen), and clinical care (Tsao) that will enable the development of chemical probes to interrogate EphA2 kinase signaling.

描述（由申请人提供）：针对特定驱动突变（例如 Bcr-Abl、EML4-ALK、突变型 EGFR 和 V600E b-raf）的蛋白激酶抑制剂具有显着的抗癌活性，正在彻底改变癌症药物的发现。新出现的证据表明，异常的 EphA2 激酶活性在许多类型的癌症中发挥着关键作用，包括乳腺癌、肺癌、卵巢癌、前列腺癌、胶质母细胞瘤和黑色素瘤，以及对各种受体酪氨酸激酶抑制剂耐药的一般机制。 Eph 系统是最大的酪氨酸激酶家族，具有 16 个 RTK 和 9 个配体，涉及多种生物学功能，从早期发育过程中的模式形成到血管生成，再到肿瘤发育过程中的失调。由于缺乏有效的、选择性的和良好表征的抑制剂，目前不可能对特定 Eph 激酶的功能进行药理学研究。在这里，我们建议使用定向药物化学方法来开发 EphA2 的有效和选择性抑制剂，并使用这些化合物使用黑色素瘤和肺癌的细胞和小鼠模型来验证 EphA2 作为潜在靶点。我们已经鉴定出以 9-14 为代表的 I 型和 II 型 ATP 竞争性抑制剂，它们对 EphA2 和其他 Eph 激酶表现出有效的活性，在这里我们建议使用结构引导的药物化学进一步优化效力、选择性和药理学特性 (Aims 1&2）。现有的和新生成的化合物将广泛分析其抗增殖活性，并与工程化的 EphA2 耐药等位基因结合使用，使用黑色素瘤和肺癌的细胞和小鼠模型来验证 EphA2 作为潜在靶点（目标 3）。我们的实验室在开发 ALK、Mps1、Erk5、mTor、LRRK2、FGFR、JNK 和 EGFR T790M 突变形式的一流抑制剂以及使用这些化合物验证新的癌症靶标方面取得了相当大的成功。为了实现这些目标，我们组建了一个世界一流的多学科团队，整合了药物化学 (Gray)、结构生物学 (Knapp)、Eph 信号传导 (Chen)、癌细胞生物学 (Benes、Chen、Tsao)、肿瘤模型 (Wong) ，Chen）和临床护理（Tsao），这将有助于开发化学探针来询问 EphA2 激酶信号传导。