Design,Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening |
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Authors: | Xin Jin Maowei Li Tingting Qiu Rilei Yu Tao Jiang |
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Affiliation: | 1.School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; (X.J.); (M.L.); (T.Q.); (R.Y.);2.Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine, Science and Technology, Qingdao 266237, China |
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Abstract: | MNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E at Ser209 to control the translation of certain mRNAs and regulate the process of cell proliferation, cell migration and invasion, etc. Development of MNK inhibitors would be an effective treatment for related diseases. We used the MarineChem3D database to identify hit compounds targeting the protein MNK1 and MNK2 through high-throughput screening. Compounds from the phorbazole family showed good interactions with MNK1, and phorbazole C was selected as our hit compound. By analyzing the binding mode, we designed and synthesized 29 derivatives and evaluated their activity against MNKs, of which, six compounds showed good inhibition to MNKs. We also confirmed three interactions between this kind of compound and MNK1, which are vital for the activity. In conclusion, we report series of novel MNK inhibitors inspired from marine natural products and their relative structure–activity relationship. This will provide important information for further developing MNK inhibitors based on this kind of structure. |
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Keywords: | MNK eIF4E phorbazole C high-throughput screening structure-activity relationship |
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