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.

项目总结/摘要 软骨病是一种罕见的骨癌，发病率约为百万分之一。肿瘤会出现在 从尾骨到颅底的脊柱沿着的任何地方。唯一可用的治疗方法是放射治疗， 手术，由于邻近大脑等重要和敏感区域，手术可能会很复杂， 脊髓没有药物被批准用于治疗脉络膜炎，因此， 目标是一个未得到满足的关键需求。未充分研究的蛋白质brachyury，基因名称TBXT，是上调， 并且是脉络膜炎的关键驱动因素和潜在的治疗脆弱性。Brachyury表示， 在大多数人体组织中的水平非常低或根本没有，这使人们相信， Brachyury将安全地靶向癌症，并在人类中具有极好的治疗窗口。Brachyury （TBXT）是一种转录因子，这是一类通常被认为不可药用的蛋白质。我们最近发现 小分子配体，结合到brachyury，铺平了道路，一种新的方法来靶向这种蛋白质， 二价降解剂分子。二价降解物，通常称为蛋白水解靶向嵌合体（PROTAC） 利用泛素-蛋白酶体系统的力量来标记蛋白质以进行降解，这导致它们的 的拔除.在这个试点项目中，我们将把我们的小分子brachyury配体转化为PROTAC文库， 试剂，并评价它们在脉络膜细胞系中降解短尾畸形的能力。为了提高我们 为了成功降解，我们将改变短尾畸形配体、接头和E3连接酶靶向部分。 该项目的成功完成将建立未充分研究的蛋白质brachyury作为药物靶点， 并为旨在确定可用于治疗这种疾病的PROTAC的大型项目奠定基础 毁灭性的罕见癌症