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

项目总结 针对致癌蛋白相互作用的药物靶向仍然是发育的圣杯 治疗研究并承诺开创人类癌症治疗的新纪元。虽然很小 分子药物发现继续提供有效的药物来靶向蛋白质中的深疏水空洞 靶点，如激酶位点，这是一种大型、平坦和复杂的地形，具有动态蛋白质相互作用的特征 表面在很大程度上仍然没有药物。我在瓦伦斯基实验室担任高级研究科学家的工作 达纳-法伯癌症研究所的林德癌症化学生物学项目涉及到另一种选择 利用碳氢化合物结合的多肽解剖和靶向癌症蛋白质相互作用的方法，该方法 概述嵌入在信号中的天然α-螺旋相互作用基序的形状、稳定性和生物活性 蛋白质。我们的研究项目集中在生成订书肽来阐明功能结合 驱动细胞凋亡阻断和病理性转录的表面和相互作用机制 人类癌症的方案，重点是去调控的bcl2家族、p53和KRAS信号转导。我们 努力通过将这些新型试剂应用于蛋白质组学来不断扩大多肽装订的用途 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环境中部署了装订的多肽，研究和靶向 致癌基因β-连环蛋白、EZH_2/EED、寡核苷酸、MUC_1-C、ATF_2和RPA。在每个项目中，新的机械论 洞察力和原型疗法已经出现。我们为蛋白质设计的光反应装订多肽 捕获、快速识别和绘制已知和未预料到的蛋白质靶标上的结合位点，从而扩展 潜在的可用药癌症蛋白质组。事实上，装订多肽作为一种新药的临床潜力 Hdm2/HDMX的第一个双重抑制剂正在进行的临床试验中反映了癌症的治疗方式 在晚期实体瘤和淋巴瘤中重新激活P53(NCT02264613)。在过去的十年里，我领导了 瓦伦斯基实验室的装订多肽合成设备和癌症化学林德计划 生物学。在这样做的过程中，我亲自负责开发和优化背后的化学 装订多肽合成，打造集咨询、生产、纯化、定量、 已推动装订多肽的不同应用和临床翻译的表征工作流程。我的 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，以及 作为Dana-Farber研究科学家，我的众多多学科协作经验奠定了基础 我非常热情地利用下一代装订多肽的潜力来影响我们的 对人类癌症的认识和治疗。

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.