The WEE1 kinase negatively regulates CDK1/2 to control DNA replication and mitotic entry. Genetic factors that determine sensitivity to WEE1 inhibitors (WEE1i) are largely unknown. A genome-wide inser...

Wee1 phosphorylates and inhibits CDK activity to inhibit mitotic entry and establish a G2 DNA damage checkpoint. Consequently, Wee1 inhibitors are in clinical trials, developed to be synthetically let...

By simulating tiny protein changes instead of screening hundreds of kinases, researchers design strong and specific Wee1 inhibitors

Small molecules promoting protein–protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN–DDB1 and WEE1 provides a model of the protein–protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

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A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (1), many of which were more selective for WEE1 over an undesirable off-target of 1, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from TP53-mutated colorectal cancer (CRC) peritoneal metastases, 34 (IC50 value of 62 nM) exhibited stronger efficacy than 1 (IC50 value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC50 value of 127 nM). Against primary CRC PDOs with TP53-WT, 34 significantly enhanced DNA damage, replication stress and apoptosis compared to 1, as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their effect on healthy and malignant cell viability.

The serine/threonine phosphatase-2 (PP2A) controls mitogen-associated signaling and DNA replication. The WEE1 protein tyrosine kinase controls S phase…

Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between WEE1 small-molecule inhibitors and defects in mRNA...

RPA is an essential ssDNA binding protein. Here, authors uncover a phosphosite on RPA70 and show that the RPA70 and RPA32 subunits cooperate through a phosphocode to reconfigure RPA domains. This sugg...

The WEE-family kinases, WEE1 and PKMYT1, play critical roles in regulating the G2/M cell cycle checkpoint to maintain genomic stability. Cancer cells with DNA damage response (DDR) deficiencies become heavily reliant on WEE1 and PKMYT1 to avert mitotic catastrophe. This dependence creates a synthetic lethality vulnerability that offers a promising therapeutic strategy. While early WEE1 inhibitors faced challenges due to toxicity, next-generation highly selective agents are now advancing through clinical trials with improved safety and efficacy. Similarly, PKMYT1 inhibitors have emerged as a complementary approach, with several candidates under clinical evaluation. This review examines the evolving mechanistic basis of synthetic lethality, with emphasis on how targeted inhibition of WEE1 or PKMYT1 exploits DDR defects to selectively induce genomic instability in cancer cells. Furthermore, we highlight recent advances in selective WEE kinase inhibitors, discuss key challenges, and explore innovative strategies to accelerate their development.