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：
9188065
负责人：
MICHAEL J ECK
金额：
$ 42.59万
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188065
关键词：
Adverse effects Allosteric Site Binding Binding Sites Biochemical Biological Assay Cell Line Cell model Cells Cetuximab Clinical Clinical Research Clinical Trials Combined Modality Therapy Coupled Crystallization Cysteine Dimerization Dose-Limiting Drug resistance Enzyme Kinetics Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Exhibits FDA approved Future Gatekeeping Gefitinib Generations Genetically Engineered Mouse Goals Gray unit of radiation dose HIV Human Hybrids Interdisciplinary Study Lead Ligands Malignant Neoplasms Malignant neoplasm of lung Medicine Mutation Non-Small-Cell Lung Carcinoma Oncogenic Patient Care Pharmaceutical Chemistry Pharmacologic Substance Pharmacology Phosphotransferases Property Protein Kinase Protein Tyrosine Kinase Proteins Pyrimidine Resistance Secondary to Site Structural Models Structure Therapeutic antibodies Toxic effect Translations Tyrosine Kinase Inhibitor Work base cancer therapy cellular engineering covalent bond design dimer drug efficacy in vivo Model inhibitor/antagonist interest kinase inhibitor mouse model mutant non-smoker nondrug therapy novel novel therapeutics pre-clinical preclinical study prevent public health relevance receptor resistance mechanism resistance mutation response screening standard of care targeted agent targeted cancer therapy targeted treatment tool translational study tumor virtual

项目摘要

DESCRIPTION (provided by applicant): Mutations in the EGFR kinase domain are a major cause of non-small cell lung cancer, and treatment with an EGFR-directed tyrosine kinase inhibitor (TKI) is the standard of care for patients with advanced EGFR-mutant lung cancer. However, resistance limits the long-term efficacy of these drugs. Understanding and overcoming acquired resistance to EGFR TKIs and to other targeted therapies is a central problem in cancer medicine. In analogy with the ability of "triple-cocktail" therapy to overcome the mutagenic repertoire of the HIV virus, we reason that simultaneous treatment with multiple agents targeting mutant EGFR may prevent emergence of resistance mutations, leading to more durable responses. However, at present suitable compounds with alternative mechanisms of action are not available. Like the vast majority of TKIs, all current EGFR TKIs target the ATP-site of the kinase. As described in our preliminary results, we are developing novel allosteric EGFR inhibitors that target a distinct pocket in the kinase. Enzyme kinetic studies and a co-crystal structure confirm their allosteric mechanism of action. These agents potently inhibit the EGFR T790M mutant, but are inactive on wild type EGFR. The distinct mechanism of action and binding site of these allosteric inhibitors, together with their lack of activity on WT EGFR and other protein kinases makes them especially attractive as candidates for combination therapy. We are a highly collaborative, multidisciplinary research team with deep interest in EGFR-mutant lung cancer and a record of successful inhibitor discovery. Our expertise spans kinase structure and mechanism (Eck, Co-PI), medicinal chemistry (Gray, Co-PI), cellular pharmacology (Jänne) and mouse models (Wong). Our goal is to develop first-in-class mutant-selective, allosteric EGFR inhibitors with single- agent activity in cellular and mouse models of EGFR-mutant lung cancer. In order to accomplish this goal, we further probe the binding repertoire of the allosteric pocket with virtual ligand discovery coupled with biochemical and cellular inhibition assays (Aim 1). We apply these tools and findings to drive optimization of these allosteric inhibitors through a focused medicinal chemistry effort (Aim 2), and we establish the efficacy of our optimized compounds in preclinical studies using genetically engineered mouse models of EGFR mutant lung cancer (Aim 3). Successful completion of these aims will provide proof of concept for a new class of targeted therapeutics for EGFR-mutant lung cancers that are resistant to all current agents.

描述（通过施用证明）：EGFR激酶结构域中的突变是非小细胞肺癌TED酪氨酸激酶抑制剂（TKI）的主要原因，这是高级EGFR肺癌肺癌的专门护理标准。癌症的疗法是癌症医学的中心问题。然而，目前具有替代机制的合适化合物，就像大多数TKIS一样，所有当前的EGFR TKIS目标是激酶的ATP。 EGFR T790M突变体的ANB型，但在野生型EGFR上不活跃。 - 肺癌和抑制剂发现的记录，药物化学（灰色，co-pi），细胞药理学（Jänne）和小鼠模型（wong） EGFR突变的肺癌。使用EGFR突变肺癌的遗传发动机小鼠慕斯（AM 3）为这些目标提供了概念证明，为EGFR-突变肺癌的新概念提供了耐药性。