ArticleACS chemical biology2016
Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Mechanisms and therapeutic opportunities of the ribotoxic stress response in cancer.Molecular oncology · 2026Review
- An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.The Journal of biological chemistry · 2026Article
- Darizmetinib (HRX215): A Promising 1st-in-Class Liver Regenerating Drug in Phase 1b/2a Clinical Development, Targeting the Stress Signaling Protein Kinase MKK4.Journal of medicinal chemistry · 2026Article
- In Silico, In Vitro, and In Vivo Evaluation of Woodfordia Fruticosa for Cardio Protection against Doxorubicin-Induced Cardiomyopathy.Chemistry & biodiversity · 2026Article
- ZAK activation at the collided ribosome.Nature · 2026Article
- ZAK kinase at the crossroads of cellular stress: functional plasticity, human pathobiology, and precision therapeutics.Frontiers in cell and developmental biology · 2026Review
- ZAKα Induces Pyroptosis of Colonic Epithelium Via the Caspase-11/GSDMD Pathway to Aggravate Colitis.Inflammation · 2025Article
- Increased Mitochondrial Superoxide Level Is Partially Associated With Vemurafenib-Induced Renal Tubular Toxicity.Basic & clinical pharmacology & toxicology · 2025Article
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- Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation.Nature communications · 2022Article
- Chemical IN04 Inhibits the Kinase Domain not the ROC Domain of LRRK1: Results from Homology Modeling and Molecular Docking.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2021Article
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- Vemurafenib Inhibits Active PTK6 inMolecular cancer therapeutics · 2019Article
- MTLD, a Database of Multiple Target Ligands, the Updated Version.Molecules (Basel, Switzerland) · 2017Article
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. ZAK is targeted by several clinically approved kinase inhibitors, and inhibition of ZAK has been reported to protect from doxorubicin-induced cardiomyopathy. On the other hand, unintended targeting of ZAK has been linked to severe adverse effects such as the development of cutaneous squamous cell carcinoma. Therefore, both specific inhibitors of ZAK, as well as anticancer drugs lacking off-target activity against ZAK, may provide therapeutic benefit. Here, we report the first crystal structure of ZAK in complex with the B-RAF inhibitor vemurafenib. The cocrystal structure displayed a number of ZAK-specific features including a highly distorted P loop conformation enabling rational inhibitor design. Positional scanning peptide library analysis revealed a unique substrate specificity of the ZAK kinase including unprecedented preferences for histidine residues at positions -1 and +2 relative to the phosphoacceptor site. In addition, we screened a library of clinical kinase inhibitors identifying several inhibitors that potently inhibit ZAK, demonstrating that this kinase is commonly mistargeted by currently used anticancer drugs.
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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.