Newman Joseph A, Gavard Angeline E, Imprachim Nergis, Aitkenhead Hazel, Sheppard Hadley E, Te Poele Robert, Clarke Paul A, Hossain Mohammad Anwar, Temme Louisa, Oh Hans J, Wells Carrow I, Davis-Gilbert Zachary W, Workman Paul, Gileadi Opher, Drewry David H
Centre for Medicines Discovery, University of Oxford, Oxford, UK.
Exscientia, Oxford, UK.
Nat Commun. 2025 Feb 14;16(1):1596. doi: 10.1038/s41467-025-56213-1.
Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low µM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches.
短尾蛋白是一种转录因子，在罕见骨癌脊索瘤的肿瘤生长中起关键作用，并且与其他实体瘤有关。短尾蛋白在健康组织中表达极低，这使其成为一个潜在的治疗靶点。不幸的是，作为一种无配体转录因子，短尾蛋白在历史上一直被认为是不可成药的。为了研究小分子对短尾蛋白的直接靶向作用，我们确定了人短尾蛋白单独以及与DNA结合时的结构。这些结构为DNA结合以及脊索瘤相关的G177D变体的背景提供了见解。我们使用晶体学片段筛选来识别短尾蛋白表面众多口袋上的热点。最后，我们对片段命中物进行后续化学研究，并描述噻唑化学系列发展为低 microM 效力结合剂的过程。因此，我们表明短尾蛋白是可配体的，并提供了一个晶体学片段筛选如何用于靶向难以用其他方法处理的蛋白类别的例子。
