Publication Date
1-16-2020
Journal
Cell Chemical Biology
DOI
10.1016/j.chembiol.2019.10.013
PMID
31735695
PMCID
PMC6980656
PubMedCentral® Posted Date
1-16-2021
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Antineoplastic Agents, Apoptosis, Cell Cycle Proteins, Cell Line, Tumor, DNA Damage, Drug Development, Female, Humans, Molecular Structure, Phthalazines, Piperazines, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proteolysis, Pyrazoles, Pyrimidinones, Thalidomide
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.
Graphical Abstract
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