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A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery

  • Qiangqiang Tao
  • Fang Fang
  • Jiaming Li
  • Yong Wang
  • Can Zhao
  • Jingtai Liang
  • Xiaodong MaEmail author
  • Hao WangEmail author
Original Research

Abstract

mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with IC50 values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 (GI50 = 4.66 μM) and HCT116 (GI50 = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.

Keywords

Drug resistance Cross talk mTOR/MEK bifunctional inhibitor mTOR kinase inhibitor Allosteric MEK inhibitor 

Notes

Acknowledgements

The authors acknowledge the financial support of the Natural Science Foundation of Anhui Province (1808085QH261), the Key Project of Natural Science Research in Universities of Anhui Province (KJ2019A1004), and University-Enterprise Cooperative Projects (2018HZ6 and 2019HZ078).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2020_2502_MOESM1_ESM.docx (478 kb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Qiangqiang Tao
    • 1
  • Fang Fang
    • 1
    • 2
  • Jiaming Li
    • 1
    • 2
  • Yong Wang
    • 1
  • Can Zhao
    • 1
  • Jingtai Liang
    • 1
  • Xiaodong Ma
    • 1
    • 2
    Email author
  • Hao Wang
    • 3
    Email author
  1. 1.School of PharmacyAnhui University of Chinese MedicineHefeiChina
  2. 2.Department of Medicinal ChemistryAnhui Academy of Chinese MedicineHefeiChina
  3. 3.Department of Clinical LaboratoryThe First Affiliated Hospital of University of Science and Technology of ChinaHefeiChina

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