Development and Characterization of a Wee1 Kinase Degrader
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Updated: Jan 3, 2026
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Published on: May 26, 2017
Zhengnian Li1, Benika J Pinch2, Calla M Olson1
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
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.
Insights
New Wee1 degraders, ZNL-02-096, offer a targeted approach to cancer therapy by degrading Wee1 while sparing PLK1. This novel strategy shows promise in overcoming limitations of existing Wee1 inhibitors, potentially reducing adverse events.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The G1/S cell cycle checkpoint is often dysregulated in cancer, increasing reliance on the G2/M checkpoint.
- Wee1 kinase is a critical regulator of the G2/M checkpoint, preventing mitotic entry by phosphorylating CDK1 at Tyr15.
- Existing Wee1 inhibitors like AZD1775 have limitations, including dose-limiting adverse events and off-target PLK1 activity.
Purpose of the Study:
- To develop novel Wee1 degraders to overcome the limitations of current Wee1 inhibitors.
- To investigate the efficacy and mechanism of a new Wee1 degrader, ZNL-02-096, in cancer cells.
Main Methods:
- Conjugation of AZD1775 to pomalidomide to create cereblon (CRBN)-binding Wee1 degraders.
- Evaluation of the lead compound ZNL-02-096 for Wee1 degradation, PLK1 sparing, and G2/M accumulation.
- Assessment of ZNL-02-096 synergy with Olaparib in ovarian cancer cells.
Main Results:
- The lead compound ZNL-02-096 effectively degrades Wee1 while sparing PLK1.
- ZNL-02-096 induces G2/M cell cycle accumulation at 10-fold lower doses compared to AZD1775.
- ZNL-02-096 demonstrates synergistic effects with Olaparib in ovarian cancer cells.
- The pharmacology of ZNL-02-096 is CRBN-dependent and distinct from AZD1775.
Conclusions:
- Selective Wee1 degraders, such as ZNL-02-096, represent a promising therapeutic strategy.
- These novel degraders offer potential advantages over traditional Wee1 inhibitors by reducing off-target effects and improving efficacy.
- Further evaluation of CRBN-dependent Wee1 degraders is warranted for cancer treatment.
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