Chern Ting-Rong, Liu Liu, Petrunak Elyse, Stuckey Jeanne A, Wang Mi, Bernard Denzil, Zhou Haibin, Lee Shirley, Dou Yali, Wang Shaomeng
Department of Medicinal Chemistry, Department of Internal Medicine, Department of Pharmacology, Department of Pathology, and Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS Med Chem Lett. 2020 May 14;11(6):1348-1352. doi: 10.1021/acsmedchemlett.0c00229. eCollection 2020 Jun 11.
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 -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.
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一直是治疗携带MLL融合基因的急性白血病或MLL白血病的有吸引力的治疗靶点。在此，我们报告了一种基于腺苷甲硫氨酸的聚焦化学文库的设计、合成和评估，该文库导致发现了直接靶向MLL SET结构域的强效小分子抑制剂。对许多这些MLL抑制剂的共晶体结构的测定表明，它们采用独特的结合模式，将MLL SET结构域锁定在开放的无活性构象中。
