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：
10316246
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/10316246
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 Lead 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 base design drug discovery human model improved in vivo inhibitor innovation member 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 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) 酪氨酸激酶结构域的体细胞突变是一种肺腺癌的常见原因。尽管针对 EGFR 突变肺的靶向治疗取得了显着进展对于癌症，治疗获得性耐药仍然是一个主要问题。了解并克服对 EGFR 酪氨酸激酶抑制剂 (TKI) 的获得性耐药性以及其他靶向治疗是癌症医学的中心问题。我们的长期目标是开发更有效的针对 EGFR 突变肺癌的耐受性更好的疗法，可产生持久的反应。我们推断同时使用多种针对突变 EGFR 的药物进行治疗可能会预防耐药性的出现突变，导致更持久的反应。然而，具有替代机制的合适化合物之前尚未采取行动。与绝大多数 TKI 一样，目前所有 EGFR TKI 都以 ATP- 激酶的位点。我们的多学科研究团队在 EGFR 突变肺癌方面拥有深厚的专业知识和成功发现抑制剂的记录。在最初的资助期内，我们开发了高效的变构抑制剂基于苯基甘氨酸支架，作为单一药物有效对抗 L858R/T790M 和体外和人类非小细胞肺癌小鼠模型中的 L858R/T790M/C797S EGFR 变体。这这些变构抑制剂的独特作用机制和结合位点，以及它们缺乏对药物的效力 WT EGFR 和其他蛋白激酶使它们作为联合治疗的候选者特别有吸引力。在本次更新中，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以提供前所未有的疗效、耐受性和持久性反应。我们通过以下方式追求这一目标具体目标如下：目标 1，我们将开发第二个化学系列的高效、突变选择性基于苯二氮卓酮支架的变构 EGFR 抑制剂。目标2，我们将设计和优化同时结合相邻 ATP 和突变 EGFR 变构位点的互补抑制剂对具有高度的积极配合性。据我们所知，高度合作的多位点抑制尚未之前曾在治疗开发的背景下进行过探索。目标3，我们将进行临床前验证 EGFR 变构抑制剂和互补 ATP 位点/变构对的研究，包括测试其体内功效在 EGFR 突变肺癌的异种移植模型中，并评估在这种情况下出现耐药性的可能性的双重目标。这些目标的成功实现将为新的治疗方法提供概念证明 EGFR突变肺癌。