Department of Chemistry, Yale University, New Haven, CT-06511.
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT-06511.
Angew Chem Int Ed Engl. 2024 Apr 2;63(14):e202316496. doi: 10.1002/anie.202316496. Epub 2024 Feb 28.
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.
Brachyury 是一种致癌转录因子，其过表达驱动脊索瘤生长。下调脊索瘤细胞中的 brachyury 已显示出治疗潜力，但作为一种转录因子，它通常被认为是“不可成药的”。鉴于直接针对 brachyury 的药理学干预已被证明困难，因此干预尝试转而针对上游激酶。最近，FDA 批准的激酶抑制剂 afatinib 已被证明可调节多种脊索瘤细胞系中的 brachyury 水平。在此，我们使用 afatinib 作为先导物，借助质谱和 X 射线晶体学，采用基于结构的药物设计方法，开发出小分子 DHC-156，它更选择性地结合 brachyury 并像 afatinib 一样强效地下调它。我们从这个新骨架中消除了激酶抑制作用，同时证明 DHC-156 诱导 brachyury 的翻译后下调，导致脊索瘤肿瘤细胞生长的不可逆转损害。通过这样做，我们证明了直接调节 brachyury 的可行性，这可能进一步开发出更有效的工具化合物和疗法。
