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：
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
项目类别：
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

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

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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.

项目摘要我们目前的CTD2网络中心发现，在药物治疗后，许多癌症都在稳定中出现细胞态耐凋亡，容易受到铁铁作用。在追求翻译这些发现的同时，以及整个网络中其他发现的发现，我们认识到CTD2网络的核心需求适应新的药物发现方法。在这里，我们描述了计算和实验进步从新颖的合成有机物中发现的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测定法。我们的策略基于这样的发现，即小分子糖可以聚集在一起两种不相关的蛋白质。我们将利用DNA-barcoded化合物发现类似药物样的化合物分子胶是：1）降解选择性，2）组织选择性和3）癌基因选择性。这个建议旨在开发新的方法来翻译难以停药癌症的CTD2网络发现采取新颖的疗法。这些方法产生的分子胶是当前无法提供的会议活动药物发现方法，并开发出蓝图以发现系统性下降的癌症脆弱性，组织限制的酶抑制剂和恢复蛋白质 - 蛋白质缔合的化合物致癌突变受损。在AIM 1中，我们将开发新的能力来识别特定的演示者蛋白并发现分子胶。在AIM 2中，我们将使用DNA-Barcoding发现新型分子胶技术。在AIM 3中，我们将确定体外和细胞中的作用机理，并参与CTD2网络以补充我们的化学生物学专业知识的中心。这些化合物将用作发射垫，以告知癌症的脆弱性以及化学优化后，在特定癌症类型中的治疗假设。该项目的成功结果包括识别新的化学物质来针对重要的通用癌症的目标，建立可用于CTD2网络的新颖而强大的资源，并可能用于毒品发现的新范式。