ArticleACS chemical biology2017
Dual Targeting of WEE1 and PLK1 by AZD1775 Elicits Single Agent Cellular Anticancer Activity.
Article in ACS chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 67 citations in OpenAlex.
- Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.Journal of medicinal chemistry · 2026Article
- Targeting WEE1 kinase: an integrated machine learning-cheminformatics framework for ultra-large-scale virtual screening and novel inhibitor discovery.Journal of computer-aided molecular design · 2026Article
- WEE1 kinase in cancer: Molecular mechanisms and inhibitor insights.EXCLI journal · 2026Review
- Current progress in targeting mitotic kinases in PDAC.RSC medicinal chemistry · 2025Review
- Differential Response and Resistance to KRAS-Targeted Therapy.Molecular carcinogenesis · 2025Review
- Preparation for mitosis requires gradual CDK1 activation.iScience · 2025Article
- Cyclin E1 overexpression sensitizes ovarian cancer cells to WEE1 and PLK1 inhibition.Oncogene · 2025Article
- New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives.Journal of medicinal chemistry · 2024Review
- Small molecule agents for triple negative breast cancer: Current status and future prospects.Translational oncology · 2024Review
- Review
- A new wave of innovations within the DNA damage response.Signal transduction and targeted therapy · 2023Review
- Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders.ACS omega · 2023Review
- Selective Wee1 Inhibitors Led to Antitumor ActivityACS medicinal chemistry letters · 2023Article
- Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells.Molecules (Basel, Switzerland) · 2023Article
- Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells.bioRxiv : the preprint server for biology · 2023Article
- Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma.Cancers · 2023Article
- Article
- Myt1 overexpression mediates resistance to cell cycle and DNA damage checkpoint kinase inhibitors.Frontiers in cell and developmental biology · 2023Article
- Applications of CRISPR/Cas technology against drug-resistant lung cancers: an update.Molecular biology reports · 2022Review
- Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth.Pharmaceuticals (Basel, Switzerland) · 2022Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Inhibition of the WEE1 tyrosine kinase enhances anticancer chemotherapy efficacy. Accordingly, the WEE1 inhibitor AZD1775 (previously MK-1775) is currently under evaluation in clinical trials for cancer in combination with chemotherapy. AZD1775 has been reported to display high selectivity and is therefore used in many studies as a probe to interrogate WEE1 biology. However, AZD1775 also exhibits anticancer activity as a single agent although the underlying mechanism is not fully understood. Using a chemical proteomics approach, we here describe a proteome-wide survey of AZD1775 targets in lung cancer cells and identify several previously unknown targets in addition to WEE1. In particular, we observed polo-like kinase 1 (PLK1) as a new target of AZD1775. Importantly, in vitro kinase assays showed PLK1 and WEE1 to be inhibited by AZD1775 with similar potency. Subsequent loss-of-function experiments using RNAi for WEE1 and PLK1 suggested that targeting PLK1 enhances the pro-apoptotic and antiproliferative effects observed with WEE1 knockdown. Combination of RNAi with AZD1775 treatment suggested WEE1 and PLK1 to be the most relevant targets for mediating AZD1775's anticancer effects. Furthermore, disruption of WEE1 by CRISPR-Cas9 sensitized H322 lung cancer cells to AZD1775 to a similar extent as the potent PLK1 inhibitor BI-2536 suggesting a complex crosstalk between PLK1 and WEE1. In summary, we show that AZD1775 is a potent dual WEE1 and PLK1 inhibitor, which limits its use as a specific molecular probe for WEE1. However, PLK1 inhibition makes important contributions to the single agent mechanism of action of AZD1775 and enhances its anticancer effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.