Abstract：
Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed \"undruggable\". Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA-approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure-based drug design approach, aided by mass-spectrometry and X-ray crystallography, to develop DHC-156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase-inhibition from this novel scaffold while demonstrating that DHC-156 induces the post-translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies.
摘要：
Brachyury是一种致癌转录因子，其过度表达驱动脊索瘤生长。脊索瘤细胞中短波的下调已经证明了治疗潜力，然而,作为转录因子，它通常被认为是“不可吸毒”。鉴于对短尾畸形的直接药物干预已被证明是困难的，干预的尝试反而针对上游激酶。最近,阿法替尼,FDA批准的激酶抑制剂，已被证明可以调节多种脊索瘤细胞系中的短枝水平。在这里，我们使用阿法替尼作为线索进行基于结构的药物设计方法，在质谱和X射线晶体学的帮助下，开发DHC-156，一种小分子，可以更有选择性地结合短枝，并像阿法替尼一样有效地下调它。我们从这种新型支架中消除了激酶抑制，同时证明了DHC-156诱导短枝的翻译后下调，从而导致脊索瘤肿瘤细胞生长的不可逆损害。在这样做的时候，我们证明了直接短波调制的可行性，可以进一步发展成更有效的工具化合物和疗法。
