Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia.

对参与染色质介导的信号传导的蛋白质进行化学抑制是一种控制染色质压缩的新兴策略，其目的是重新编程表达网络以改变疾病状态。蛋白质甲基转移酶构成参与基因表达的表观遗传控制的蛋白质家族之一，并代表一类新的治疗靶点。蛋白质赖氨酸甲基转移酶 DOT1L 在异常位点的募集是导致急性淋巴和髓性白血病（尤其是婴儿）的常见机制，而药物抑制 DOT1L 可以延长混合谱系白血病小鼠模型的生存期。更好地了解 DOT1L 抑制的结构化学将加速改进化合物的开发。在此，我们报告在辅因子产物 S-腺苷同型半胱氨酸（SAH，SAM 依赖性甲基转移酶抑制剂）的关键位置添加单个卤素原子可导致针对 DOT1L 的效力增加 8 倍，并降低针对 DOT1L 的活性。其他蛋白质和非蛋白质甲基转移酶。我们解析了 DOT1L 与 Bromo-deaza-SAH 复合物的晶体结构，并合理化了观察到的效果。这一发现揭示了一种简单的策略，可将 DOT1L 的选择性和效力设计到所有甲基转移酶共享的辅因子的腺苷支架中，并可用于开发针对混合谱系白血病的临床候选药物。