Development and Characterization of a Wee1 Kinase Degrader.
Cell Chem Biol
; 27(1): 57-65.e9, 2020 01 16.
Article
em En
| MEDLINE
| ID: mdl-31735695
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Pirimidinonas
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Talidomida
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Proteínas Tirosina Quinases
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Proteínas de Ciclo Celular
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Inibidores de Proteínas Quinases
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Proteólise
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Desenvolvimento de Medicamentos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article