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

项目摘要/摘要 脊索瘤是一种罕见的骨癌，发病率约为百万分之一。肿瘤可能会出现 脊椎上的任何地方，从尾骨到颅底。唯一可用的治疗方法是放射治疗和 手术，手术可能会很复杂，因为邻近重要和敏感的区域，如大脑和 脊髓。没有被批准用于治疗脊索瘤的药物，因此，确定可用药 目标是一个关键的未得到满足的需求。未被研究的蛋白质brachyury，基因名为tbxt，在 脊索瘤是脊索瘤的关键驱动力和潜在的治疗脆弱性。短视表达的是 在大多数人体组织中处于非常低的水平或根本不存在，这为调节 短程化疗将安全地针对癌症，并在人类身上有一个极好的治疗窗口。短兵相接 (TBXT)是一种转录因子，这是一类通常被认为不可下药的蛋白质。我们最近确认了 与短尾鱼结合的小分子配体，为利用 二价降解剂分子。二价降解物，通常称为针对嵌合体的蛋白质降解(PROTAC) 利用泛素-蛋白酶体系统的力量来标记蛋白质进行降解，这导致了它们 移走。在这个试点项目中，我们将把我们的小分子短链配体转化为一个PROTAC文库 并评估它们在脊索瘤细胞系中降解短链尿素的能力。为了提高我们的机会 如果降解成功，我们将改变短链配体、连接子和E3连接酶的靶向部分。 该项目的成功完成将使未被研究的短毛蛋白成为可用于治疗的药物靶标。 脊索瘤并为更大的项目奠定基础，这些项目旨在识别可用于治疗脊索瘤的PROTAC 毁灭性的罕见癌症。

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.