Studies of mutant-selective allosteric inhibitors of EGFR for non-small cell lung cancer

EGFR突变选择性变构抑制剂治疗非小细胞肺癌的研究

基本信息

批准号：
9909661
负责人：
Tyler Steven Beyett
金额：
$ 6.49万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-04 至 2023-06-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909661
关键词：
Address Affect Allosteric Site Applications Grants Area Binding Binding Sites Biochemical Budgets Cancer Biology Cellular biology Charge Chemicals Chemistry Clinic Clinical Collaborations Combined Modality Therapy Complex Crystallization Dana-Farber Cancer Institute Development Drug resistance Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evaluation Foundations Future Gefitinib Goals Growth In Situ Link Malignant Neoplasms Malignant neoplasm of lung Manuscripts Mediating Methods Molecular Mutation NCI Center for Cancer Research Nature Non-Small-Cell Lung Carcinoma Oncogenic Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphotransferases Postdoctoral Fellow Predisposition Prevalence Protein Biochemistry Protein Tyrosine Kinase Proteins Refractory Research Resistance Resistance development Signal Transduction Site Solid Structure Synthesis Chemistry System Therapeutic Training Tyrosine Kinase Inhibitor Variant Work Writing assay development cancer cell cancer pharmacology cancer type clinically relevant design effective therapy experience in vivo inhibitor/antagonist insight kinase inhibitor medical schools mortality mutant new therapeutic target novel novel therapeutics post-doctoral training programs resistance mechanism resistance mutation small molecule structural biology student mentoring success symposium synergism technical writing therapeutic development tumor

项目摘要

PROJECT ABSTRACT Lung cancer is the most common and highest mortality type of cancer and is frequently the result of activating mutations to the epidermal growth factor receptor (EGFR). Due to the emergence of resistance mutations in patients treated with EGFR inhibitors, allosteric inhibitors targeting EGFR mutants have shown promise as the next generation of therapeutics. With their distinct binding sites, canonical, ATP-competitive inhibitors can bind simultaneously and cooperatively with allosteric inhibitors to synergistically kill cancer cells in vivo. Combination of EGFR inhibitors with different mechanisms of action represents a new paradigm for targeting tumors that are refractory to current monotherapies through the exploitation of cooperative binding principles. The long-term goal of this project is to understand the mechanism of action of cooperative kinase inhibitor binding to oncogenic and drug resistant variants of EGFR to aid in the development of novel combination therapies for EGFR-driven lung cancers. Structural and pharmacological methods will be used to define cooperative binding mechanisms and synergy of different combinations of ATP-competitive and allosteric inhibitors in the context of clinically-relevant EGFR variants to understand the effects of these mutations on co-binding. Insights garnered from these studies will be used to rationally design and synthesize complimentary pairs of inhibitors with enhanced cooperativity. The resulting inhibitor combinations may be able to overcome common resistance mutations or display enhanced selectivity for oncogenic variants of EGFR over wild-type. The proposed project will take place at the Dana-Farber Cancer Institute (DFCI), a leading research center for cancer research, and will benefit greatly from its strong translational therapeutics program. The proposed project takes into account the trainee’s strengths in protein biochemistry and structural biology while providing training in medicinal chemistry and cancer biology. Through DFCI’s affiliation with Harvard Medical School, the trainee will take courses in cancer cell biology and synthetic chemistry, present at departmental seminars and conferences, and mentor students. The sponsors of this project are experts in the fields of EGFR pharmacology and kinase inhibitor chemistry and will allow the trainee to assist in writing relevant grant proposals to provide training in technical writing and budgeting. The trainee will be the primary contact with regard to project collaborations and will be in charge of initiating and coordinating manuscripts describing the results of this project.

项目摘要肺癌是最常见和最高的荒野类型的癌症，并且是自由的，这是激活的结果表皮生长因子受体（EGFR）的突变。用EGFR抑制剂治疗的患者，靶向EGFR突变体的变构抑制剂已显示出有望为下一代及其独特的约束力的治疗学同时与同类抑制剂合作的协同作用在体内杀死癌细胞具有不同作用机制的EGFR抑制剂的代表通过剥削合作结合原理对当前的单层反应。该项目的长期目标是了解合作激酶抑制剂结合的作用机理 EGFR的致癌和抗药性变体有助于开发新型组合疗法 EGFR驱动的肺癌将使用结构和药理学方法定义合作结合在ATP竞争者和异常的不同组合的机制和协同背景下与临床上的EGFR变体了解MTIL的效果从研究中将用于合理设计和合成符合人增强的合作社。 EGFR的致癌变体比野生型的杂种选择性提高。该项目将在领先的研究中心达纳 - 弗拉伯癌症研究所（DFCI）举行癌症研究将使其静止治疗计划受益考虑到学员在蛋白质生物化学和结构性生物中的优势在医学化学和癌症生物学上。将参加癌细胞生物学生物学和合成化学的课程会议和导师的学生。和激酶抑制剂化学，并将willow tracheee willow to whoseee撰写Revant Grant提供技术写作和预算培训。协作，并将负责启动和协调手稿描述该项目的结果。