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

项目摘要 肺癌是最常见和死亡率最高的癌症类型，并且通常是活化的结果。 表皮生长因子受体（EGFR）突变。由于耐药突变的出现， 对于接受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作为 下一代的治疗方法典型的ATP竞争性抑制剂具有不同的结合位点， 同时和协同地与变构抑制剂在体内协同杀死癌细胞。组合 具有不同作用机制的EGFR抑制剂代表了靶向肿瘤的新范例， 通过利用合作约束原则，目前的单一疗法难以治疗。 本项目的长期目标是了解协同激酶抑制剂结合的作用机制 EGFR的致癌和耐药变体，以帮助开发用于治疗癌症的新的联合疗法。 EGFR驱动的肺癌。将使用结构和药理学方法来定义协同结合 ATP-竞争性和变构抑制剂的不同组合的机制和协同作用， 临床相关的EGFR变体，以了解这些突变对共结合的影响。获得的见解 将用于合理设计和合成互补的抑制剂对， 增强合作性。由此产生的抑制剂组合可能能够克服共同的阻力 突变或相对于野生型显示出对EGFR致癌变体的增强的选择性。 拟议的项目将在丹娜-法伯癌症研究所（DFCI）进行，DFCI是一个领先的研究中心， 癌症研究，并将大大受益于其强大的转化治疗方案。拟建项目 在提供培训的同时，考虑到学员在蛋白质生物化学和结构生物学方面的优势 在药物化学和癌症生物学方面。通过DFCI与哈佛医学院的联系， 将参加癌细胞生物学和合成化学课程，出席部门研讨会， 会议和指导学生。该项目的申办者是EGFR药理学领域的专家 和激酶抑制剂化学，并将允许受训者协助编写相关的赠款提案， 技术写作和预算编制方面的培训。培训生将是项目的主要联系人 他将负责发起和协调描述该项目结果的手稿。

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.