The mixed-lineage leukemia (MLL) protein, also known as MLL1, is a lysine methyltransferase specifically responsible for methylation of histone 3 lysine 4. MLL has been pursued as an attractive therapeutic target for the treatment of acute leukemia carrying the MLL fusion gene or MLL leukemia. Herein, we report the design, synthesis, and evaluation of an S-adenosylmethionine-based focused chemical library which led to the discovery of potent small-molecule inhibitors directly targeting the MLL SET domain. Determination of cocrystal structures for a number of these MLL inhibitors reveals that they adopt a unique binding mode that locks the MLL SET domain in an open, inactive conformation.

中文翻译：

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发现MLL甲基转移酶的有效小分子抑制剂。

混合谱系白血病（MLL）蛋白，也称为MLL1，是一种赖氨酸甲基转移酶，专门负责组蛋白3赖氨酸4的甲基化。MLL已被视为具有MLL融合基因或MLL白血病。在此，我们报告了基于S-腺苷甲硫氨酸的重点化学文库的设计，合成和评估，该文库导致发现了直接靶向MLL SET域的强效小分子抑制剂。对许多这些MLL抑制剂的共晶结构的测定表明，它们采用了独特的结合模式，将MLL SET域锁定在开放的，无活性的构象中。