ArticleProceedings of the National Academy of Sciences of the United States of America2021
Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- PIP4K2A depletion suppresses AKT signaling and enhances chemotherapy sensitivity in T-cell lymphoblastic lymphoma cells.Biochemical and biophysical research communications · 2026Article
- Article
- A proximity-labeling map of PI5P4K phosphoinositide kinases interaction networks.The Journal of biological chemistry · 2026Article
- Structural basis for high-affinity inhibitor binding to lipid kinases PIP4K2A and PIP4K2B.Acta crystallographica. Section D, Structural biology · 2026Article
- PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.Cell reports · 2025Article
- PI5P4K inhibitors: promising opportunities and challenges.The FEBS journal · 2025Review
- Anticancer Potential of Azatetracyclic Derivatives: In Vitro Screening and Selective Cytotoxicity of Azide and Monobrominated Compounds.Molecules (Basel, Switzerland) · 2025Article
- Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.Science signaling · 2024Article
- PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma.Cancers · 2024Article
- The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K).RSC medicinal chemistry · 2023Article
- Identification of ARUK2002821 as an isoform-selective PI5P4Kα inhibitor.RSC medicinal chemistry · 2023Article
- Beyond PI3Ks: targeting phosphoinositide kinases in disease.Nature reviews. Drug discovery · 2023Review
- PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1.Nature communications · 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
- 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
- PIP kinases: A versatile family that demands further therapeutic attention.Advances in biological regulation · 2023Article
- Lipid kinases PIP5Ks and PIP4Ks: potential drug targets for breast cancer.Frontiers in oncology · 2023Review
- Targeting phosphoinositide signaling in cancer: relevant techniques to study lipids and novel avenues for therapeutic intervention.Frontiers in cell and developmental biology · 2023Article
- 25 Years of PI5P.Frontiers in cell and developmental biology · 2023Review
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase α and β (PI5P4Kα and PI5P4Kβ) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kα/β kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kαβ inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer 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.