Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
Angew Chem Int Ed Engl. 2018 Dec 10;57(50):16302-16307. doi: 10.1002/anie.201810617. Epub 2018 Nov 16.
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.
YEATS 结构域（YD）蛋白是药物发现中新兴的一类表观遗传靶标。这些修饰赖氨酸结合蛋白的失调与癌症的发生和进展有关。本文报道了首个小分子化学探针 SGC-iMLLT 的发现和表征，该探针可用于 MLLT1（ENL/YEATS1）和 MLLT3（AF9/YEATS3）的 YD。SGC-iMLLT 是一种强效且选择性的 MLLT1/3-组蛋白相互作用抑制剂。在其他人类 YD 蛋白（YEATS2/4）和溴结构域中观察到极好的选择性。此外，我们的探针还显示了对 MLLT1 和 MLLT3 的细胞靶标结合。还报告了与 MLLT1 YD 的第一个小分子 X 射线共晶结构。这种首创的探针分子可用于了解 MLLT1/3 相关生物学和小分子 YD 抑制剂的治疗潜力。
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