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A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1

Yumi Matsui1, Isao Yasumatsu1, Ken Ichi Yoshida2

  • 1Daiichi Sankyo RD Novare Co. Ltd, 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.

Acta Crystallographica. Section F, Structural Biology Communications
|March 3, 2018
PubMed

Insights

Mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) drive cancer by affecting translation initiation. A novel inhibitor stabilizes Mnk1 in its inactive form, blocking cancer cell growth.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) regulate translation initiation via eukaryotic translation initiation factor 4E phosphorylation.
  • Mnk1/2 activity is crucial for tumorigenesis but not essential for normal cell function, indicating therapeutic potential.

Purpose of the Study:

  • To elucidate the structural basis for Mnk1 inhibition.
  • To guide the development of novel Mnk1-targeted cancer therapies.

Main Methods:

  • Discovery of a novel Mnk1 inhibitor.
  • Determination of the crystal structure of Mnk1 in complex with the inhibitor.

Main Results:

  • The inhibitor binds to the autoinhibited state of Mnk1.
  • Stabilization of the Mnk-specific DFD motif in the DFD-out conformation.
  • Prevention of Mnk1 activation and inhibition of kinase activity.

Conclusions:

  • The identified inhibitor effectively blocks Mnk1 activity by stabilizing its autoinhibited conformation.
  • These findings offer a structural foundation for designing potent Mnk1 inhibitors for cancer treatment.
Keywords:
DS12881479MAPK-interacting kinase 1Mnk1inactive conformationskinasekinase inhibitorstransferases

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