Development and Characterization of a Wee1 Kinase Degrader

• Published in: Cell chemical biology Vol. 27; no. 1; pp. 57 - 65.e9
• Main Authors: Li, Zhengnian, Pinch, Benika J., Olson, Calla M., Donovan, Katherine A., Nowak, Radosław P., Mills, Caitlin E., Scott, David A., Doctor, Zainab M., Eleuteri, Nicholas A., Chung, Mirra, Sorger, Peter K., Fischer, Eric S., Gray, Nathanael S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 16.01.2020
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; cancer; cell cycle; Cell Cycle Proteins - metabolism; Cell Line, Tumor; DNA Damage; Drug Development; Female; Humans; mitosis; Molecular Structure; Phthalazines - chemistry; Phthalazines - pharmacology; Piperazines - chemistry; Piperazines - pharmacology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - metabolism; Proteolysis - drug effects; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; synergy; targeted protein degradation; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Thalidomide - pharmacology; WEE1; WEE1; synergy; cell cycle; DNA damage; targeted protein degradation; cancer; mitosis
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2019.10.013

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. [Display omitted] •A selective Wee1 degrader was generated by conjugating pomalidomide to AZD1775•Wee1 degradation induced G2/M accumulation at lower doses than Wee1 inhibition•Wee1 degradation synergized with Olaparib in ovarian cancer cells Li, Pinch et al. develop and characterize the first selective Wee1 degrader, ZNL-02-096, by linking the clinical candidate inhibitor, AZD1775, to the cereblon-binding ligand, pomalidomide. They demonstrate that ZNL-02-096 exhibits cereblon-dependent pharmacology, induces G2/M phase accumulation and apoptosis at lower doses than AZD1775, and synergizes with Olaparib.