Development and Characterization of a Wee1 Kinase Degrader

  • Cell Chem Biol. 2020 Jan 16;27(1):57-65.e9. doi: 10.1016/j.chembiol.2019.10.013.
Zhengnian Li  1 ,  Benika J Pinch  2 ,  Calla M Olson  1 ,  Katherine A Donovan  1 ,  Radosław P Nowak  1 ,  Caitlin E Mills  3 ,  David A Scott  1 ,  Zainab M Doctor  4 ,  Nicholas A Eleuteri  1 ,  Mirra Chung  3 ,  Peter K Sorger  3 ,  Eric S Fischer  1 ,  Nathanael S Gray  5
Affiliations
  • 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: [email protected].
PMID: 31735695 DOI: 10.1016/j.chembiol.2019.10.013
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.
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