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Both HDACs and Mnks play important role in translating multiple oncogenic signaling pathways during oncogenesis. As HDAC and Mnk are highly expressed in a variety of tumors; thus simultaneous inhibit HDAC and Mnk can increase the inhibition of tumor cell proliferation and provide a new way of inhibiting tumor growth. Based on the previous work and the merge pharmacophore method; we designed and synthesized a series of 4,6-disubstituted pyrido[3,2-<i>d</i>]pyrimidine derivatives as HDAC and Mnk dual inhibitors. Among them; compound <b>A12</b> displayed good HDAC and Mnk inhibitory activity. In vitro antiproliferative assay; compound <b>A12</b> exhibited the best antiproliferative activity against human prostate cancer PC-3 cells. Docking study revealed that the pyrido[3,2-<i>d</i>]pyrimidine framework and hydroxamic acid motif of compound <b>A12</b> were essential for maintaining the activity of HDAC and Mnk. These result indicated that <b>A12</b> was a potent Mnk /HDAC inhibitor and will be further researched.