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Cell Chem Biol. 2020 Jan 16;27(1):57-65.e9. doi: 10.1016/j.chembiol.2019.10.013. Epub 2019 Nov 14.

Development and Characterization of a Wee1 Kinase Degrader.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Department of Chemical Biology, Harvard University, Cambridge, MA, USA.
3
Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Electronic address: nathanael_gray@dfci.harvard.edu.

Abstract

The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses than AZD1775, and synergizes with Olaparib in ovarian cancer cells. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from AZD1775, which justifies further evaluation of selective Wee1 degraders.

KEYWORDS:

DNA damage; WEE1; cancer; cell cycle; mitosis; synergy; targeted protein degradation

PMID:
31735695
PMCID:
PMC6980656
[Available on 2021-01-16]
DOI:
10.1016/j.chembiol.2019.10.013

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