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 T. Jensen, Gunda I. Georg, Ernst Schönbrunn

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 - Sep 28 2017

Bibliographical note

Funding Information:
We thank the Moffitt Chemical Biology Core for use of the protein crystallography facility (National Cancer Institute Grant P30-CA076292) and the Southeast Regional Collaborative Access Team (SER-CAT, University of Georgia) for synchrotron data collection. We also thank William Goodheart and Paula Cranfill (Moffitt Cancer Center) for assistance with large scale protein production. This work was supported by the National Institute for Child Health & Human Development (NICHD) Grants U01-HD076542, U54-HD055744, and HHSN275201300017C.

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