ArticleMolecular cancer therapeutics2010
Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor.
Article in Molecular cancer therapeutics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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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
51 citing papers in PubMed, 76 citations in OpenAlex.
- Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D.JCO precision oncology · 2024Trial
- Target and Agent Prioritization for the Children's Oncology Group-National Cancer Institute Pediatric MATCH Trial.Journal of the National Cancer Institute · 2017Trial
- PDPK1 activates BIRC3 via NFKB1 to promote radiotherapy resistance in lung adenocarcinoma.Cancer cell international · 2026Article
- Stalling the Enemy: Targeting Nsp13 for Next-Generation SARS-CoV-2 Antivirals.International journal of molecular sciences · 2026Article
- Review
- Phosphoinositide-dependent kinase 1 (PDK1) in cancer: molecular insights and therapeutic strategies.Frontiers in chemistry · 2026Review
- In vivo antitumor activity of PHT-427 inhibitor-loaded polymeric nanoparticles in head and neck squamous cell carcinoma.Drug delivery · 2025Article
- Discovery, Optimization, and Anticancer Activity of Lipid-Competitive Pleckstrin Homology Domain-Containing Family A Inhibitors.Journal of medicinal chemistry · 2025Article
- Small Molecule Modulator of the mTORC2 Pathway Discovered from a DEL Library Designed to Bind to Pleckstrin Homology Domains.ACS chemical biology · 2024Article
- PHT427 as an effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitor restored the susceptibility of meropenem againstFrontiers in microbiology · 2023Article
- Beyond controlling cell size: functional analyses of S6K in tumorigenesis.Cell death & disease · 2022Review
- The Landscape of PDK1 in Breast Cancer.Cancers · 2022Review
- Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids.Structure (London, England : 1993) · 2021Article
- Antitumor Activity of Nanoparticles Loaded with PHT-427, a Novel AKT/PDK1 Inhibitor, for the Treatment of Head and Neck Squamous Cell Carcinoma.Pharmaceutics · 2021Article
- Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling.International journal of molecular sciences · 2020Review
- Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells.Cancers · 2019Article
- An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors.Cancer research · 2019Article
- Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3β/FOXO1 Signaling and Improves Glucose Metabolism.Nutrients · 2018Article
- A microfluidics platform for combinatorial drug screening on cancer biopsies.Nature communications · 2018Article
- Protein Kinase Targets in Breast Cancer.International journal of molecular sciences · 2017Review
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non-small cell lung cancer. When given >5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity.
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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.