J Med Chem. 2019 Jul 11;62(13):6015-6034. doi: 10.1021/acs.jmedchem.9b00021. Epub 2019 Jun 22.
Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound (M-89). M-89 binds to menin with a value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
抑制 menin-混合谱系白血病 (MLL) 蛋白-蛋白相互作用是治疗携带 MLL 融合（MLL 白血病）的急性白血病的一种很有前途的新治疗策略。我们在此描述了基于结构的设计、合成和评估一类新型小分子 menin-MLL 相互作用抑制剂（以下简称 menin 抑制剂）的研究结果。我们的努力发现了高活性的 menin 抑制剂，例如化合物 (M-89)。M-89 与 menin 的结合值为 1.4 nM，并能以低纳摩尔浓度有效地与细胞内的 menin 蛋白结合。M-89 在携带 MLL 融合的 MV4;11 和 MOLM-13 白血病细胞系中的细胞生长抑制浓度分别为 25 和 55 nM，与缺乏 MLL 融合的 HL-60 白血病细胞系相比具有 >100 倍的选择性。M-89 与 menin 复合物的共晶结构的确定为它们的高亲和力相互作用提供了结构基础。进一步优化 M-89 可能会为治疗 MLL 白血病提供一类新的治疗方法。
