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

• 批准号: 10505307
• 负责人: PAUL ANDREW CLEMONS
• 金额: $ 93.6万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505307
• 关键词: 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; Complement; Complex; Computer Analysis; DNA; 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; 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

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.

项目摘要 我们目前的CTD 2网络中心发现，许多癌症在药物治疗后， 细胞状态抵抗凋亡和易受铁凋亡。在努力转化这些调查结果的同时， 以及整个网络的其他发现，我们认识到对CTD 2网络的核心需求 to adapt适应new新methods方法of drug药物discovery发现.在这里，我们描述了计算和实验的进展， 小分子粘合剂和分子胶的发现， 化学、DNA条形码、基于亲和力的筛选后富集条形码的计算分析，以及 化学生物学分析。我们的策略基于这样一个发现，即小分子胶水可以将 这两种蛋白质在其他情况下不会结合。我们将利用DNA条形码化合物来发现类似药物的化合物， 分子胶：1）降解选择性，2）组织选择性，3）癌基因选择性。这项建议 旨在开发新的方法来转化CTD 2网络发现的难以药物治疗的癌症脆弱性 to novel新therapeutics疗法.这些方法产生的分子胶具有目前无法获得的活性， 药物发现方法，并制定蓝图，发现系统的癌症降解剂 脆弱性，组织限制性酶抑制剂和恢复蛋白质-蛋白质关联的化合物 因致癌突变而受损在目标1中，我们将开发新的能力来识别特定的呈递蛋白 并发现分子胶。在目标2中，我们将使用DNA条形码发现新型分子胶 技术.在目标3中，我们将确定体外和细胞中的作用机制，并参与CTD 2网络 中心，以补充我们的化学生物学专业知识。这些化合物将作为发射台， 癌症的脆弱性，并在化学优化，在特定的癌症类型的治疗假设。 该项目的成功成果包括确定新的化学物质，以靶向重要的遗传物质， 癌症靶点，建立一个新的和强大的资源可用于CTD 2网络，并可能 一种新的药物发现模式。