Journal of Chinese Pharmaceutical Sciences ›› 2018, Vol. 27 ›› Issue (10): 686-695.DOI: 10.5246/jcps.2018.10.070

• Original articles • Previous Articles     Next Articles

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

Can Li, Hongyue Li, Jing Sun, Dandan Xi, Chao Wang, Lei Liang, Fengrong Xu, Yan Niu*, Ping Xu*   

  1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
  • Received:2018-05-31 Revised:2018-07-17 Online:2018-10-30 Published:2018-09-10
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  • Supported by:

    National Natural Science Fund of China (Grant No. 21172012), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120001110010) and Beijing Natural Science Foundation of China (Grant No. 7162110).


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(3H)-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.

Key words: 5-Benzyl-2-phenylpyrimidin-4(3H)-one, MEK1 inhibitor, Docking

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