ArticleCell chemical biology2020
Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors.
Article in Cell chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 55 citations in OpenAlex.
- 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
- 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
- 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
- Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia.International journal of molecular sciences · 2023Article
- 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
- Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c.G3 (Bethesda, Md.) · 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
- Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.Angewandte Chemie (International ed. in English) · 2023Article
- Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1.Journal of medicinal chemistry · 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
- 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
- Identification of a chemical probe for lipid kinase phosphatidylinositol-5-phosphate 4-kinase gamma (PI5P4Kγ).Current research in chemical biology · 2023Article
Corrections and comments
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Authors and funding
21 authors at 3 institutions in 2 countries.
Funding
Abstract
The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.
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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.