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）：蛋白激酶抑制剂的戏剧性抗癌活性，该蛋白激酶抑制剂针对特定的驱动器突变，例如BCR- ABL，EML4-ALK，突变EGFR和V600E B-RAF正在革新癌症药物发现。新兴的证据表明，异常的EPHA2激酶活性在许多类型的癌症中起关键作用，包括乳腺癌，肺，卵巢，前列腺，胶质细胞瘤和黑色素瘤，以及对各种受体酪氨酸激酶的抑制剂耐药性的一般机制。 EPH系统是最大的酪氨酸激酶家族，具有16个RTK和9种配体，并且与一系列的生物学功能有关，从早期发育期间的模式形成到血管生成到血管生成到肿瘤发育期间的消除调节。由于缺乏有效，选择性和特征性良好的抑制剂，目前不可能对特定EPH激酶功能的药理询问。在这里，我们提出使用定向的中学化学方法来开发EPHA2的有效和选择性抑制剂，并使用这些化合物将EPHA2验证为使用黑色素瘤和肺癌的细胞和鼠模型来验证EPHA2作为潜在靶标。我们已经确定了I型和II型ATP竞争性抑制剂的体现，这些抑制剂由9-14示例，这些抑制剂对EPHA2和其他EPH激酶具有有效的活性，在这里，我们建议使用结构指导的药物化学对效力，选择性和药理学性质进行进一步优化（目标1＆2）。现有和新生成的化合物将以抗增殖活性进行广泛介绍，并结合工程的EPHA2药物抗药性等位基因，以验证Epha2作为使用黑色素瘤和肺癌的细胞模型和鼠模型的潜在靶标（AIM 3）。我们的实验室在开发ALK，MPS1，ERK5，MTOR，LRRK2，FGFRS，JNKS和T790M突变体形式的ALK，MPS1，ERK5，MTOR，LRK2，LRRK2，LRRK2，LRRK2，FGFRS和T790M突变体形式以及使用这些化合物验证新癌症靶标方面取得了很大的成功。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，该团队整合了药物化学（灰色），结构生物学（KNAPP），EPH信号（Chen），癌细胞生物学（Benes，Chen，Tsao），肿瘤模型（Wong，Chen）和临床护理（TSAO），这些概率将启用化学效果。