Structure-based design and synthesis of 5-benzyl-2-phenylpyrimidin-4(3H)-one derivatives as novel MEK1 inhibitors

5-苄基-2-苯基嘧啶-4(3H)-酮类新型MEK抑制剂基于结构的设计与合成（英文）

Previous studies have shown that Ras/Raf/MEK/ERK signaling pathway is up-regulated in almost all cancer cells.Blocking of this pathway by MEK inhibition is an efficient therapeutic approach of cancer.In the present study,we described the discovery of 5-benzyl-2-phenylpyrimidin-4（3 H）-one as a novel skeleton of allosteric MEK inhibitor.All acquired target compounds exhibited modest potency to inhibit MEK1 in Raf-MEK cascading assay,and docking studies revealed that the binding mode of the most potent compound（SJ3） was very similar to that of the well known diarylamine-based inhibitor（PD0325901）.The results provided valuable guidance for further optimizations on this novel scaffold to achieve druggable molecules.

Ras/Raf/MEK/ERK通路在人类的多种肿瘤中均表现异常活化,通过抑制MEK激酶阻断该通路是有效的癌症治疗策略。本文描述了5-苄基-2-苯基嘧啶-4(3H)-酮类作为新型MEK变构抑制剂骨架的设计与合成。所得目标化合物在Raf-MEK级联实验中表现出中等的MEK1抑制效力,对接研究结果显示活性最好的化合物SJ3的结合模式与常见的二芳胺类抑制剂PD0325901的结合模式非常相似。这些结果为基于该新型母核结构的进一步设计和优化并最终获得成药性分子提供了有力的依据。