Bivalent degraders of the understudied transcription factor TBXT for the rare cancer chordoma

正在研究的罕见癌症脊索瘤转录因子 TBXT 的二价降解剂

• 批准号: 10725821
• 负责人: David Harold Drewry
• 金额: $ 15.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10725821
• 关键词: Adult; Area; Binding; Binding Proteins; Biological; Biological Assay; Brachyury protein; Brain; Breast; Cell Line; Cells; Chemistry; Chordoma; Complex; DNA; Data; Development; Disease; Dose; Enzymes; Excision; Exhibits; Family; Foundations; Gene Expression; Genes; Genetic Transcription; Hand; Human; Incidence; Individual; Label; Length; Libraries; Ligand Binding; Ligands; Lung; Malignant Bone Neoplasm; Malignant Neoplasms; Medicine; Mutate; Names; Operative Surgical Procedures; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Pilot Projects; Play; Positioning Attribute; Prostate; Protac; Proteins; Protocols documentation; Radiation; Reagent; Role; Signal Pathway; Spinal Cord; Spottings; Structure; Surface; System; Therapeutic; Therapeutic Intervention; Time; Tissues; Ubiquitin; Ubiquitination; United States National Institutes of Health; Vertebral column; Western Blotting; X-Ray Crystallography; cancer cell; design; druggable target; experimental study; flexibility; human tissue; improved; interest; multicatalytic endopeptidase complex; notochord development; novel strategies; overexpression; programs; protein degradation; rare cancer; response; scaffold; skull base; small molecule; tool; transcription factor; tumor; ubiquitin-protein ligase

Project Summary / Abstract Chordoma is a rare bone cancer with an incidence of about 1 in a million people. The tumors can appear anywhere along the spine, from the tailbone to the skull base. The only available treatments are radiation and surgery, and surgery can be complicated due to adjacency to important and sensitive areas like the brain and spinal cord. No medicines are approved for the treatment of chordoma and, as such, identification of druggable targets is a critical unmet need. The understudied protein brachyury, gene name TBXT, is upregulated in chordoma and is both a key driver and potential therapeutic vulnerability of chordoma. Brachyury is expressed at very low levels or not at all in most human tissues, providing confidence that compounds that modulate brachyury will safely target the cancer and have an excellent therapeutic window in humans. Brachyury (TBXT) is a transcription factor, a class of proteins often considered undruggable. We have recently identified small molecule ligands that bind to brachyury, paving the way for a new approach to target this protein using bivalent degrader molecules. Bivalent degraders, often called proteolysis targeting chimeras (PROTACs) harness the power of the ubiquitin-proteasome system to label proteins for degradation and this leads to their removal. In this pilot project, we will convert our small molecule brachyury ligands into a library of PROTAC reagents and evaluate their ability to degrade brachyury in chordoma cell lines. To improve our chances of successful degradation we will vary the brachyury ligand, the linker, and the E3 ligase targeting moiety. Successful completion of this project will establish the understudied protein brachyury as a druggable target for chordoma and set the stage for larger projects designed to identify PROTACs that can be used to treat this devastating rare cancer.

项目摘要 /摘要 Chordoma是一种罕见的骨癌，发病率约为100万人。肿瘤可能会出现 沿着脊柱的任何地方，从尾骨到颅底。唯一可用的治疗方法是辐射和 由于与大脑和敏感区域（如大脑和 脊髓。没有药物被批准用于治疗脊全瘤，因此可以识别可药物 目标是一个至关重要的未满足需求。研究了研究的蛋白质Brachyury，基因名称TBXT，在 脊索瘤既是脊全瘤的关键驱动因素，也是潜在的治疗脆弱性。 Brachyury表示 在大多数人体组织中，在非常低的水平或根本不高的水平上，提供了调节化合物的信心 Brachyury将安全针对癌症，并在人类中具有出色的治疗窗口。 Brachyury （TBXT）是转录因子，一类蛋白质通常被认为是不可能的。我们最近确定了 与Brachyury结合的小分子配体，为使用该蛋白靶向这种蛋白质的新方法铺平了道路 二价降解分子。二价降解者，通常称为靶向嵌合体的蛋白水解（Protac） 利用泛素 - 蛋白酶体系统的力量标记蛋白质以降解，这导致了它们 移动。在这个试点项目中，我们将小分子的小分子体育配体转换为Protac库 试剂并评估其在脊髓瘤细胞系中降解胸肌的能力。提高我们的机会 成功的降解我们将改变Brachyury配体，接头和E3连接酶的靶向部分。 该项目的成功完成将确定研究不足的蛋白质Brachyury作为可吸毒的目标 弦瘤并为大型项目奠定了舞台，旨在识别可用于治疗此事 破坏稀有癌症。