Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M

EGFR T790M 新型突变选择性变构抑制剂的发现和优化

基本信息

批准号：
10534760
负责人：
MICHAEL J ECK
金额：
$ 48.07万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534760
关键词：
Active Sites Allosteric Site Antibodies Automobile Driving Binding Binding Sites Biochemical Biological Assay Cancer Etiology Cell model Cetuximab Chemicals Clinical Trials Combined Modality Therapy Dimerization Drug Targeting Drug resistance Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Equilibrium Erlotinib Exhibits Extracellular Domain Family Future Gefitinib Generations Genetically Engineered Mouse Goals Grant Human In Situ In Vitro Interdisciplinary Study Ligands Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Medicine Mutation Non-Small-Cell Lung Carcinoma Oncologist Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Point Mutation Probability Progress Reports Protein Kinase Resistance Series Site Somatic Mutation Structural Biologist Structure Testing Toxic effect Translations Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Validation Variant Work Xenograft Model acquired treatment resistance design drug discovery human model improved in vivo inhibitor innovation member monomer mouse model multidisciplinary mutant novel novel drug class novel strategies novel therapeutic intervention pharmacokinetics and pharmacodynamics pre-clinical prevent receptor binding resistance mechanism resistance mutation response scaffold standard of care success synergism targeted agent targeted treatment therapeutic development tumor

项目摘要

Abstract: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of lung adenocarcinoma. Despite marked advances in targeted therapies for EGFR-mutant lung cancer, treatment-acquired resistance remains a major problem. Understanding and overcoming acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) and to other targeted therapies is a central problem in cancer medicine. Our long term goal is to develop more effective and better tolerated therapies for EGFR mutant lung cancer that yield durable responses. We reason that simultaneous treatment with multiple agents targeting mutant EGFR may prevent emergence of resistance mutations, leading to more durable responses. However, suitable compounds with alternative mechanisms of action have not previously been available. Like the vast majority of TKIs, all current EGFR TKIs target the ATP- site of the kinase. Our multidisciplinary research team has deep expertise in EGFR-mutant lung cancer and a record of successful inhibitor discovery. In the initial grant period, we developed highly potent allosteric inhibitors based on a phenylglycine scaffold that are effective as single agents against L858R/T790M and L858R/T790M/C797S EGFR variants in vitro and in mouse models of human non-small cell lung cancer. The distinct mechanism of action and binding site of these allosteric inhibitors, together with their lack of potency on WT EGFR and other protein kinases, makes them especially attractive as candidates for combination therapy. In this renewal, we will discover whether compounds that target the ATP and allosteric sites can indeed synergize to deliver unprecedented efficacy, tolerability and durability of responses. We pursue this goal through the following specific aims: Aim 1, We will develop a second chemical series of highly potent, mutant-selective allosteric EGFR inhibitors based on a benzodiazepinone scaffold. Aim 2, We will design and optimize complementary pairs of inhibitors that simultaneously bind the adjacent ATP and allosteric sites of mutant EGFR with a high degree of positive cooperativity. To our knowledge, highly cooperative, multi-site inhibition has not been previously explored in the context of therapeutic development. Aim 3, We will perform pre-clinical validation of allosteric EGFR inhibitors and complementary ATP-site/allosteric pairs, including testing their in vivo efficacy in xenograft models of EGFR mutant lung cancer and assessing the potential for resistance to arise in the context of dual targeting. Successful execution of these aims will provide proof of concept for a new therapeutic approach in EGFR mutant lung cancer.

抽象的：表皮生长因子受体（EGFR）的酪氨酸激酶结构域中的体细胞突变为A 肺腺癌的常见原因。尽管针对EGFR突变肺的目标疗法取得了明显进步癌症，可获得的抗药性仍然是一个主要问题。理解并克服对EGFR酪氨酸激酶抑制剂（TKI）的耐药性其他靶向疗法是癌症医学中的核心问题。我们的长期目标是发展更有效以及对EGFR突变肺癌的更好耐受疗法，可产生持久反应。我们认为用靶向突变体EGFR的多种代理人同时治疗可能会阻止出现抗药性突变，导致更耐用的响应。但是，具有替代机制的合适化合物动作以前尚未可用。像绝大多数TKI一样，所有当前的EGFR TKI都针对ATP- 激酶的位点。我们的多学科研究团队在EGFR突变肺癌和A 成功抑制剂发现的记录。在最初的授予期内，我们开发了高度有效的变构抑制剂基于苯基甘氨酸支架，该支架可作为对L858R/T790M的单一药物有效 L858R/T790M/C797S EGFR在体外和人类非小细胞肺癌的小鼠模型中。这这些变构抑制剂的不同作用机理和结合位点，以及它们缺乏效力 WT EGFR和其他蛋白激酶使它们成为组合疗法的候选者特别有吸引力。在此续约中，我们将发现针对ATP和变构位点的化合物是否确实可以协同作用，提供前所未有的疗效，耐受性和响应的耐用性。我们通过以下具体目的：AIM 1，我们将开发第二个化学系列高度有效的突变选择性基于苯二氮卓酮支架的变构EGFR抑制剂。 AIM 2，我们将设计和优化同时结合相邻ATP和突变体EGFR的变构位点的抑制剂对互补对具有高度的积极合作。据我们所知，高度合作，多站点的抑制尚未以前是在治疗开发的背景下进行的。 AIM 3，我们将执行临床前验证变构EGFR抑制剂和互补的ATP位点/变构对，包括测试其体内功效在EGFR突变肺癌的异种移植模型中，并评估了在这种情况下产生抗性的潜力双向目标。这些目标的成功执行将为一种新的治疗方法提供概念证明在EGFR突变肺癌中。