Targeted Inhibition of EGFR Dimerization

EGFR 二聚化的靶向抑制

• 批准号: 8949665
• 负责人: Eileen J Kennedy
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949665
• 关键词: Binding Sites; Cancer cell line; Cell Line; Clinic; Clinical; Colorectal Cancer; Computer Simulation; Development; Diagnostic Neoplasm Staging; Dimerization; EGF gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Family member; Goals; Growth; Head and Neck Cancer; Homo; Human; Knowledge; Ligand Binding; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Mediating; Mission; Molecular; Molecular Conformation; Monitor; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Outcome; Pathogenesis; Patients; Peptides; Phosphorylation; Phosphotransferases; Play; Property; Public Health; Receptor Protein-Tyrosine Kinases; Research; Resistance; Role; Signal Transduction; Site; Specificity; Structure; Surface; Testing; Therapeutic; Translating; Work; arm; base; cancer therapy; design; extracellular; improved; innovation; insight; kinase inhibitor; malignant breast neoplasm; novel; novel strategies; prevent; protein protein interaction; public health relevance; receptor; receptor expression; resistance mechanism; targeted treatment; therapeutic target; therapy resistant; tool; tumor; tumor initiation; tumor progression

 DESCRIPTION (provided by applicant): There is a significant need for development of alternative strategies for targeted kinase inhibition. As an alternative for selective kinase targeting, this study is focused on the development of chemically constrained peptides that target allosteric activation mechanisms. This proposal is the crucial first step in the development of a powerful new tool towards developing peptide-based allosteric inhibitors of kinases. The long-term goal of this work is to develop allosteric effectors that target kinase activation as it relates to cancer. The overall objective for this application is to develop novel, peptide-based compounds that disrupt protein-protein interactions (PPIs) involved in allosteric activation of EGFR. It is the central hypothesis that by targeting alternative conserved surfaces of EGFR that regulate PPIs rather than the ATP or EGF binding sites, EGFR can be effectively inhibited and this targeting strategy may retain activity in patients that are unresponsive to current EGFR-targeted therapies. The rationale underlying the proposed project is that the knowledge gained by developing allosteric EGFR inhibitors has the potential to translate into innovative, highly specific targeting strategies for successful inhibition of diverse kinases in cancer. This hypothesis will be tested by pursuing two specific aims: 1) Evaluate inhibitory properties of constrained EGFR dimerization arm peptides in different classes of resistance to EGFR-targeted therapies; and 2) Optimize inhibitory properties of constrained peptides mimicking the dimerization arm of EGFR. The expected outcomes of this work will be significant. First, this study will validate the concept that allosteric kinase activation mechanisms can be targeted for inhibition. Next, it will be determined whether these alternative targeting approaches can inhibit lung cancer cell lines that either differ in EGFR expression levels or are resistant to EGFR-targeted therapies by monitoring formation of ErbB homo- and heterodimers. ErbB inhibition will be extensively characterized in cell lines with various resistance mechanisms. In silico approaches will also be applied to optimize ligand binding and efficacy and will validate the compounds biochemically. Ultimately, the synthetic strategies developed in this study can also be applied to diverse protein-protein interaction surfaces. This work will contribute significantly to our understanding of designing compounds that target kinase allostery. The research proposed in this application is innovative because it represents a new and substantive departure from the status quo by proposing that PPIs play a significant role in kinase activation and therefore allosteric activation mechanisms can be targeted using alternative synthetic strategies including novel compounds included in this study that target and inhibit the PPI interface. This contribution is significant because it will undoubtedly reveal new, alternative approaches for inhibition of EGFR and other receptor tyrosine kinases.

 描述（由申请人提供）：非常需要开发靶向激酶抑制的替代策略。作为选择性激酶靶向的替代方案，本研究的重点是开发靶向变构激活机制的化学约束肽。这项提议是发展中至关重要的第一步， 开发基于肽的激酶变构抑制剂的强大新工具。这项工作的长期目标是开发针对与癌症相关的激酶激活的变构效应物。本申请的总体目标是开发新的基于肽的化合物，其破坏参与EGFR变构活化的蛋白质-蛋白质相互作用（PPI）。中心假设是，通过靶向调节PPI而不是ATP或EGF结合位点的EGFR替代保守表面，EGFR可以被有效抑制，并且这种靶向策略可以在对当前EGFR靶向治疗无反应的患者中保留活性。拟议项目的基本原理是，通过开发变构EGFR抑制剂获得的知识有可能转化为创新的，高度特异性的靶向策略，成功抑制癌症中的多种激酶。该假设将通过追求两个特定目标进行检验：1）评价受约束的EGFR二聚化臂肽在对EGFR靶向疗法的不同类别的抗性中的抑制特性;和2）优化模拟EGFR的二聚化臂的受约束肽的抑制特性。这项工作的预期成果将是重要的。首先，这项研究将验证的概念，变构激酶激活机制可以针对抑制。接下来，将通过监测ErbB同源二聚体和异源二聚体的形成来确定这些替代靶向方法是否可以抑制EGFR表达水平不同或对EGFR靶向疗法具有抗性的肺癌细胞系。ErbB抑制将在具有各种耐药机制的细胞系中广泛表征。计算机模拟方法也将用于优化配体结合和功效，并将在生物化学上验证化合物。最终，本研究中开发的合成策略也可以应用于不同的蛋白质-蛋白质相互作用表面。这项工作将大大有助于 我们对设计靶向激酶变构的化合物的理解。本申请中提出的研究具有创新性，因为它代表了一种新的实质性偏离现状，提出PPI在激酶激活中发挥重要作用，因此可以使用替代合成策略（包括本研究中包含的靶向和抑制PPI界面的新型化合物）靶向变构激活机制。这一贡献是重要的，因为它无疑将揭示抑制EGFR和其他受体酪氨酸激酶的新的替代方法。