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Molecular Pharmacology

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Research ArticleArticle

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2

Sunita K.C. Basnet, Sarah Diab, Raffaella Schmid, Mingfeng Yu, Yuchao Yang, Todd Alexander Gillam, Theodosia Teo, Peng Li, Tom Peat, Hugo Albrecht and Shudong Wang
Molecular Pharmacology November 2015, 88 (5) 935-948; DOI: https://doi.org/10.1124/mol.115.100131
Sunita K.C. Basnet
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Sarah Diab
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Raffaella Schmid
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Mingfeng Yu
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Yuchao Yang
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Todd Alexander Gillam
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Theodosia Teo
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Peng Li
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Tom Peat
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Hugo Albrecht
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Shudong Wang
Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.K.C.B., S.D., R.S., M.Y., Y.Y., T.A.G., T.T., P.L., H.A., S.W.); and CSIRO Biosciences Program, Parkville, Victoria, Australia (T.P.)
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Abstract

Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a nontoxic and effective strategy for cancer therapy. However, a lack of specific Mnk inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of a novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II inhibitors. A selection of 66 compounds was tested for Mnk1 and Mnk2 inhibition, and 9 out of 20 active compounds showed type III interaction with an allosteric site of the proteins. Most of the type III inhibitors exhibited dual Mnk1 and Mnk2 activities and demonstrated potent antiproliferative properties against the MV4-11 acute myeloid leukemia cell line. Interestingly, ATP-/substrate-competitive inhibitors were found to be highly selective for Mnk2, with little or no activity for Mnk1. Our study suggests that Mnk1 and Mnk2 share a common structure of the allosteric inhibitory binding site but possess different structural features of the ATP catalytic domain. The findings will assist in the future design and development of Mnk targeted anticancer therapeutics.

Footnotes

    • Received May 27, 2015.
    • Accepted August 11, 2015.
  • This work is supported by the Australia Government National Health and Medical Research Council [Grant 1050825] and South Australian Health and Medical Research Institute, Beat Cancer Project Principal Cancer Research Fellowship to S.W.

  • dx.doi.org/10.1124/mol.115.100131.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (5)
Molecular Pharmacology
Vol. 88, Issue 5
1 Nov 2015
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Research ArticleArticle

Allosteric Inhibition of Mnks

Sunita K.C. Basnet, Sarah Diab, Raffaella Schmid, Mingfeng Yu, Yuchao Yang, Todd Alexander Gillam, Theodosia Teo, Peng Li, Tom Peat, Hugo Albrecht and Shudong Wang
Molecular Pharmacology November 1, 2015, 88 (5) 935-948; DOI: https://doi.org/10.1124/mol.115.100131

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Research ArticleArticle

Allosteric Inhibition of Mnks

Sunita K.C. Basnet, Sarah Diab, Raffaella Schmid, Mingfeng Yu, Yuchao Yang, Todd Alexander Gillam, Theodosia Teo, Peng Li, Tom Peat, Hugo Albrecht and Shudong Wang
Molecular Pharmacology November 1, 2015, 88 (5) 935-948; DOI: https://doi.org/10.1124/mol.115.100131
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