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Design, synthesis and biological evaluation of MNK-PROTACs

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Abstract

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) can regulate cellular mRNA translation by controlling the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), which plays an important role in tumor initiation, development, and metastasis. Although small-molecule MNK inhibitors have made significant breakthroughs in the treatment of various malignancies, their clinical application can be limited by drug resistance, target selectivity and other factors. The strategy of MNK-PROTACs which selectively degrades MNK kinases provides a new approach for developing small-molecule drugs for related diseases. In this study, DS33059, a small-molecule compound modified based on the ongoing clinical trials drug ETC-206, was chosen as the target protein ligand. A series of novel MNK-PROTACs were designed, synthesized and evaluated biological activity. Several compounds showed good inhibitory activities against MNK1/2. Besides, compounds exhibited moderate to excellent anti-proliferative activity in A549 and TMD-8 cells in vitro. In particular, compound II-5 significantly inhibited A549 (IC50 = 1.79 μM) and TMD-8 (IC50 = 1.07 μM) cells. The protein degradation assay showed that compound II-5 had good capability to degrade MNK1. The MNK-PROTACs strategy represents a new direction in treating tumors and deserves further exploration.

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Funding

This study was supported by the Lingang Laboratory (Grant No. LG202103-02-08).

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Author notes

  1. Xue Sun and Qingyun Wu have contributed equally to this work.

Authors and Affiliations

  1. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China

    Xue Sun, Dezhong Guan & Jinpei Zhou

  2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China

    Qingyun Wu, Hong Bu, Yifeng Pei, Shi Guo & Huibin Zhang

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  1. Xue Sun
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Contributions

SX and WQY wrote the manuscript, designed the study, performed experiments and analyzed the data. BH designed the study, performed experiments and analyzed the data. PYF carried out the research on molecular docking and analyzed the data. GDZ and GS provided materials and important suggestions. ZJP and ZHB designed the study, supervised the study and revised the manuscript.

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Correspondence to Jinpei Zhou or Huibin Zhang.

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Sun, X., Wu, Q., Bu, H. et al. Design, synthesis and biological evaluation of MNK-PROTACs. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10776-7

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