Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

Jin Yi Zhu, Rebecca A. Cuellar, Norbert Berndt, Hee Eun Lee, Sanne H. Olesen, Mathew P. Martin, Jeffrey Jensen, Gunda I. Georg, Ernst Schönbrunn

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency, suggesting complex mechanisms of activation. A series of crystal structures reveal unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775. Kinome profiling and cellular studies demonstrate that, in addition to Wee1 and Wee2, MK-1775 is an equally potent inhibitor of the polo-like kinase PLK1. Several previously unrecognized inhibitors of Wee kinases were discovered and characterized. Combined, the data provide a comprehensive view on the catalytic and structural properties of Wee kinases and a framework for the rational design of novel inhibitors thereof.

Original languageEnglish (US)
Pages (from-to)7863-7875
Number of pages13
JournalJournal of Medicinal Chemistry
Volume60
Issue number18
DOIs
StatePublished - 2017

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Phosphotransferases
Phosphorylation
Protein Kinases
Cell Cycle
Pharmaceutical Preparations
MK 1775

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Zhu, J. Y., Cuellar, R. A., Berndt, N., Lee, H. E., Olesen, S. H., Martin, M. P., ... Schönbrunn, E. (2017). Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. Journal of Medicinal Chemistry, 60(18), 7863-7875. https://doi.org/10.1021/acs.jmedchem.7b00996

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. / Zhu, Jin Yi; Cuellar, Rebecca A.; Berndt, Norbert; Lee, Hee Eun; Olesen, Sanne H.; Martin, Mathew P.; Jensen, Jeffrey; Georg, Gunda I.; Schönbrunn, Ernst.

In: Journal of Medicinal Chemistry, Vol. 60, No. 18, 2017, p. 7863-7875.

Research output: Contribution to journalArticle

Zhu, JY, Cuellar, RA, Berndt, N, Lee, HE, Olesen, SH, Martin, MP, Jensen, J, Georg, GI & Schönbrunn, E 2017, 'Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors', Journal of Medicinal Chemistry, vol. 60, no. 18, pp. 7863-7875. https://doi.org/10.1021/acs.jmedchem.7b00996
Zhu, Jin Yi ; Cuellar, Rebecca A. ; Berndt, Norbert ; Lee, Hee Eun ; Olesen, Sanne H. ; Martin, Mathew P. ; Jensen, Jeffrey ; Georg, Gunda I. ; Schönbrunn, Ernst. / Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 18. pp. 7863-7875.
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