ArticleThe Biochemical journal2015
The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site.
Article in The Biochemical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 44 citations in OpenAlex.
- A proximity-labeling map of PI5P4K phosphoinositide kinases interaction networks.The Journal of biological chemistry · 2026Article
- Orthosteric-allosteric dual inhibitors of PI5P4Kγ with potent antitumor activity in non-small cell lung cancer.Journal of advanced research · 2026Article
- Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.Journal of medicinal chemistry · 2026Review
- Application of chemical similarity and bioisosteres to find allosteric inhibitors of type 2 lipid kinase γ.Scientific reports · 2025Article
- Structure-Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-Pharmaceuticals (Basel, Switzerland) · 2025Article
- PI5P4K inhibitors: promising opportunities and challenges.The FEBS journal · 2025Review
- Beyond PI3Ks: targeting phosphoinositide kinases in disease.Nature reviews. Drug discovery · 2023Review
- Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.Angewandte Chemie (International ed. in English) · 2023Article
- Development of potent and selective degraders of PI5P4Kγ.European journal of medicinal chemistry · 2023Article
- PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.Science advances · 2023Article
- The Identification of Potent, Selective, and Brain Penetrant PI5P4Kγ Inhibitors as In Vivo-Ready Tool Molecules.Journal of medicinal chemistry · 2023Article
- SGC-CAMKK2-1: A Chemical Probe for CAMKK2.Cells · 2023Article
- Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Targeting phosphoinositide signaling in cancer: relevant techniques to study lipids and novel avenues for therapeutic intervention.Frontiers in cell and developmental biology · 2023Article
- Small molecules targeting endocytic uptake and recycling pathways.Frontiers in cell and developmental biology · 2023Review
- Lipid kinases PIP5Ks and PIP4Ks: potential drug targets for breast cancer.Frontiers in oncology · 2023Review
- PIP kinases: A versatile family that demands further therapeutic attention.Advances in biological regulation · 2023Article
- Identification of a chemical probe for lipid kinase phosphatidylinositol-5-phosphate 4-kinase gamma (PI5P4Kγ).Current research in chemical biology · 2023Article
- Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.Journal of medicinal chemistry · 2022Article
- Mechanistic roles of mutant p53 governing lipid metabolism.Advances in biological regulation · 2022Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
NIH-12848 (NCGC00012848-02), a putative phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) inhibitor, was explored as a tool for investigating this enigmatic, low activity, lipid kinase. PI5P4K assays in vitro showed that NIH-12848 inhibited PI5P4Kγ with an IC50 of approximately 1 μM but did not inhibit the α and β PI5P4K isoforms at concentrations up to 100 μM. A lack of inhibition of PI5P4Kγ ATPase activity suggested that NIH-12848 does not interact with the enzyme's ATP-binding site and direct exploration of binding using hydrogen-deuterium exchange (HDX)-MS (HDX-MS) revealed the putative PI5P-binding site of PI5P4Kγ to be the likely region of interaction. This was confirmed by a series of mutation experiments which led to the identification of a single PI5P4Kγ amino acid residue that can be mutated to its PI5P4Ks α and β homologue to render PI5P4Kγ resistant NIH-12848 inhibition. NIH-12848 (10 μM) was applied to cultured mouse principal kidney cortical collecting duct (mpkCCD) cells which, we show, express PI5P4Kγ that increases when the cells grow to confluence and polarize. NIH-12848 inhibited the translocation of Na⁺/K⁺-ATPase to the plasma membrane that occurs when mpkCCD cells grow to confluence and also prevented reversibly their forming of 'domes' on the culture dish. Both these NIH-12848-induced effects were mimicked by specific RNAi knockdown of PI5P4Kγ, but not that of PI5P4Ks α or β. Overall, the data reveal a probable contribution of PI5P4Kγ to the development and maintenance of epithelial cell functional polarity and show that NIH-12848 is a potentially powerful tool for exploring the cell physiology of PI5P4Ks.
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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.