Translating novel cancer targets and mechanisms from the CTD^2 Network using molecular glues

使用分子胶从 CTD^2 网络转化新的癌症靶点和机制

基本信息

批准号：
10704124
负责人：
PAUL ANDREW CLEMONS
金额：
$ 91.73万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704124
关键词：
Acceleration Address Affinity Alleles Antineoplastic Agents Apoptosis Bar Codes Binding Biochemical Biological Assay Biological Models Biology Brachyury protein Catalytic Domain Cell Line Cell model Cells Chemicals Chordoma Collaborations Complement Complex Computer Analysis DNA DNA analysis Data Dependence Detection Enzyme Inhibitor Drugs Event Future Genetic Glues Hot Spot Impairment In Vitro Libraries Ligation MADH3 gene MADH4 gene Malignant Bone Neoplasm Malignant Neoplasms Methods Modeling Molecular Mutation Oncogenes Oncogenic Organic Chemistry Outcome PIK3CG gene Pharmaceutical Preparations Pharmacotherapy Phospholipids Procedures Property Proteins Reagent Resistance Resources Role Structure-Activity Relationship System Technology Therapeutic Tissues Toxic effect Translating Translations Work base biophysical properties cancer cell cancer type computational pipelines dashboard data portal drug discovery interest mutant next generation novel novel therapeutic intervention novel therapeutics phospholipid-hydroperoxide glutathione peroxidase protein protein interaction recruit screening small molecule small molecule therapeutics therapeutic development therapy resistant transcription factor treatment response tumor ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Our current CTD2 Network Center discovered that many cancers, following drug treatment, emerge in a stable cell state resistant to apoptosis and vulnerable to ferroptosis. While pursuing efforts to translate these findings, and the findings of other discoveries throughout the Network, we recognized a central need for the CTD2 Network to adapt new methods of drug discovery. Here, we describe computational and experimental advances in the discovery of small-molecule binders and molecular glues emerging from the novel use of synthetic organic chemistry, DNA barcoding, computational analyses of enriched barcodes following affinity-based screens, and chemical biology assays. We base our strategy on the discovery that small-molecule glues can bring together two proteins that do not otherwise associate. We will exploit DNA-barcoded compounds to discover drug-like molecular glues that are: 1) degradation-selective, 2) tissue-selective, and 3) oncogene-selective. This proposal aims to develop novel methods to translate CTD2 Network discoveries of difficult-to-drug cancer vulnerabilities towards novel therapeutics. The methods yield molecular glues that confer activities not available by current drug-discovery methods, and to develop a blueprint to discover systematically degraders for cancer vulnerabilities, tissue-restricted enzyme inhibitors, and compounds that restore protein–protein associations impaired by oncogenic mutation. In Aim 1, we will develop novel capabilities to identify specific presenter proteins and to discover molecular glues. In Aim 2, we will discover novel molecular glues using DNA-barcoding technology. In Aim 3, we will determine mechanism of action in vitro and in cells and engage CTD2 Network Centers to complement our chemical biology expertise. These compounds will serve as launching pads to inform cancer vulnerabilities and, upon chemical optimization, therapeutic hypotheses in specific cancer types. Successful outcomes of this project include the identification of new chemical matter to target important genetic targets in cancer, establishment of a novel and powerful resource available to the CTD2 Network, and potentially a new paradigm for drug discovery.

项目概要我们目前的 CTD2 网络中心发现，许多癌症在经过药物治疗后，会以稳定的状态出现。在努力转化这些发现的同时，细胞状态对细胞凋亡具有抵抗力并且易受铁死亡的影响。以及整个网络中其他发现的结果，我们认识到 CTD2 网络的核心需求在这里，我们描述了药物发现的计算和实验进展。合成有机物的新用途发现了小分子粘合剂和分子胶化学、DNA 条形码、基于亲和力筛选后富集条形码的计算分析，以及我们的策略基于小分子胶可以聚集在一起的发现。我们将利用 DNA 条形码化合物来发现类似药物。分子胶具有：1）降解选择性，2）组织选择性，3）癌基因选择性。旨在开发新方法来转化 CTD2 网络对难以药物治疗的癌症漏洞的发现这些方法产生的分子胶具有目前无法实现的活性。药物发现方法，并制定系统地发现癌症降解剂的蓝图脆弱性、组织限制性酶抑制剂以及恢复蛋白质-蛋白质关联的化合物在目标 1 中，我们将开发识别特定呈递蛋白的新能力。在目标 2 中，我们将使用 DNA 条形码发现新型分子胶。在目标 3 中，我们将确定体外和细胞内的作用机制并参与 CTD2 网络。补充我们化学生物学专业知识的中心将作为提供信息的发射台。癌症的脆弱性，以及基于化学优化的特定癌症类型的治疗假设。该项目的成功成果包括鉴定出针对重要遗传物质的新化学物质癌症目标，建立可供 CTD2 网络使用的新颖且强大的资源，并有可能药物发现的新范例。