The Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL, USA.
Department of Pharmacology, Northwestern University, Chicago, IL, USA.
Chem Biol Drug Des. 2019 Oct;94(4):1813-1823. doi: 10.1111/cbdd.13585. Epub 2019 Aug 4.
Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation-based induced-fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP-binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure-based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.
神经元细胞外信号调节激酶（Mnk1 和 2）是丝裂原活化蛋白激酶途径的下游效应因子，调节真核起始因子 4E 的磷酸化。Mnk 途径的参与在急性髓系白血病（AML）的白血病发生中至关重要，Mnk 抑制剂在体外和体内具有很强的抗白血病特性，这表明靶向 Mnk 激酶可能为治疗 AML 提供一种新方法。在这里，我们报告了一种基于突变的诱导契合的计算机筛选方法的开发和应用，以鉴定新型 Mnk 抑制剂。通过暂时突变 Mnk1 晶体结构中阻塞 ATP 结合位点的氨基酸，同时进行已知抑制剂的对接模拟，构建了 Mnk1 结构模型。命中化合物在 Mnk 生化和细胞测定中显示出活性，包括急性髓系白血病祖细胞。这种方法将能够进一步进行基于结构的新型 Mnk 抑制剂的合理药物设计，并可能为靶向这种激酶提供新的治疗方法。
