Journal
CELL CHEMICAL BIOLOGY
Volume 27, Issue 1, Pages 57-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2019.10.013
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Funding
- NIH F31 Fellowship [CA225066]
- NIH [5 T32 GM00730641, 5 T32 GM095450-04]
- Chleck Family Foundation
- NIH/NCI [HL127365]
- NIH R01 [CA218278 01A1]
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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.
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