Stapled Peptides for Protein Interaction Research and Therapeutic Targeting in Human Cancer

用于人类癌症蛋白质相互作用研究和治疗靶向的钉合肽

• 批准号: 9221493
• 负责人: Gregory Howard Bird
• 金额: $ 26.41万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221493
• 关键词: ATF2 gene; Apoptosis; Apoptotic; BCL2 gene; Binding; Binding Sites; Biochemistry; Biology; Cancer Biology; Cancer Patient; Cellular biology; Chemicals; Chemistry; Clinical; Clinical Trials; Collaborations; Complex; Consultations; Dana-Farber Cancer Institute; Developmental Therapeutics Program; EZH2 gene; Epigenetic Process; Family; Genetic Transcription; Human; Hydrocarbons; KRAS2 gene; Laboratories; Lymphoma; MDM2 gene; Malignant Neoplasms; Maps; Modality; Mucin 1 protein; Oncogenic; Pathologic; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Phosphotransferases; Production; Protein Dynamics; Protein Engineering; Proteins; Proteome; Proteomics; Reagent; Research; Scientist; Series; Shapes; Signal Transduction; Signaling Protein; Site; Solid Neoplasm; Surface; TP53 gene; Therapeutic; Therapeutic Human Experimentation; Training; Translations; Work; beta catenin; cell motility; clinical application; drug discovery; experience; in vivo; inhibitor/antagonist; insight; multidisciplinary; next generation; novel; novel therapeutics; programs; prototype; small molecule; structural biology; targeted agent; therapeutic target; tool

PROJECT SUMMARY Pharmacologic targeting of oncogenic protein interactions remains the holy grail of developmental therapeutics research and holds promise to deliver a new era of treatments for human cancer. Whereas small molecule drug discovery continues to deliver effective agents for targeting deep, hydrophobic holes in protein targets such as kinase sites, the large, flat, and complex terrain that characterizes dynamic protein interaction surfaces remains largely undrugged. My work as a Senior Research Scientist in the Walensky laboratory and Linde Program in Cancer Chemical Biology at the Dana-Farber Cancer Institute involves an alternative approach to dissecting and targeting cancer protein interactions using hydrocarbon-stapled peptides, which recapitulate the shape, stability, and bioactivity of natural α-helical interaction motifs embedded within signaling proteins. Our research programs focus on generating stapled peptides to elucidate the functional binding surfaces and interaction mechanisms that drive the apoptotic blockades and pathologic transcriptional programs of human cancer, emphasizing deregulated BCL-2 family, p53, and KRAS signal transduction. We strive to continually broaden the utility of peptide stapling by adapting these novel reagents for proteomic discovery, structural analyses, cellular mechanism of action studies, and in vivo application. Through a series of collaborations, we have also deployed stapled peptides in diverse cancer contexts, studying and targeting oncogenic β-catenin, EZH2/EED, Olig2, MUC1-C, ATF2, and RPA. In each of these projects, new mechanistic insights and prototype therapeutics have emerged. Our photoreactive stapled peptides designed for protein capture, rapidly identify and map binding sites on known and unanticipated protein targets, expanding the potentially druggable cancer proteome. Indeed, the clinical potential of stapled peptides as a new drug modality for cancer is reflected by ongoing clinical trials of the first dual inhibitor of HDM2/HDMX for reactivating p53 in advanced solid tumors and lymphomas (NCT02264613). Over the last ten years, I have led the stapled peptide synthesis facility of the Walensky laboratory and Linde Program in Cancer Chemical Biology. In doing so, I have been personally responsible for developing and optimizing the chemistry behind stapled peptide synthesis, and creating an integrated consultation, production, purification, quantitation, and characterization workflow that has fueled diverse applications and clinical translation of stapled peptides. My graduate training in chemistry, my postdoctoral work at the intersection of chemistry and cancer biology, and my numerous and multidisciplinary collaborative experiences as a Dana-Farber Research Scientist, underlie my tremendous enthusiasm for harnessing the potential of next-generation stapled peptides to impact both our understanding and treatment of human cancer.

项目摘要 致癌蛋白相互作用的药理学靶向仍然是发展的圣杯 治疗研究，并有望为人类癌症治疗带来新时代。而小 分子药物的发现继续为靶向蛋白质中的深疏水孔提供有效的药物 激酶位点等靶点，即表征动态蛋白质相互作用的大而平的复杂地形 表面基本上没有凹凸不平。我在瓦伦斯基实验室担任高级研究科学家， 丹娜-法伯癌症研究所的林德癌症化学生物学项目涉及一种替代方案， 使用烃钉合肽解剖和靶向癌症蛋白质相互作用的方法， 概括的形状，稳定性，和天然α-螺旋相互作用基序嵌入信号转导 proteins.我们的研究项目集中在产生钉合肽，以阐明功能结合 表面和相互作用机制，驱动凋亡阻滞和病理转录 人类癌症的程序，强调失调的BCL-2家族，p53和KRAS信号转导。我们 通过使这些新试剂适用于蛋白质组学， 发现、结构分析、细胞作用机制研究和体内应用。通过一系列 在合作中，我们还在不同的癌症背景下部署了钉合肽， 致癌β-连环蛋白、EZH 2/EED、Olig 2、MUC 1-C、ATF 2和RPA。在每一个项目中，新的机械 出现了新的见解和原型疗法。我们为蛋白质设计的光反应性钉合肽 捕获、快速识别和绘制已知和非预期蛋白质靶点的结合位点， 潜在的药物治疗癌症蛋白质组。事实上，钉合肽作为一种新药的临床潜力 目前正在进行的第一种HDM 2/HDMX双重抑制剂的临床试验反映了这种治疗癌症的方式。 在晚期实体瘤和淋巴瘤中重新激活p53（NCT 02264613）。在过去的十年里，我领导了 Walensky实验室和Linde癌症化学项目的钉合肽合成设施 生物学在这样做的过程中，我一直亲自负责开发和优化背后的化学反应， 钉合肽合成，并创建一个集成的咨询，生产，纯化，定量， 这是一个独特的表征工作流程，推动了钉合肽的多种应用和临床翻译。我 化学研究生培训，我在化学和癌症生物学交叉点的博士后工作， 我作为丹娜-法伯研究科学家的众多多学科合作经验， 我对利用下一代钉合肽的潜力来影响我们的 了解和治疗人类癌症。