ArticleCell death and differentiation2010
The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane.
Article in Cell death and differentiation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 106 citations in OpenAlex.
- Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies.Leukemia research · 2013Trial
- Multi-omics profiling identifies triciribine as a biomarker-guided antimetabolite therapy for acute lymphoblastic leukemia.NPJ precision oncology · 2026Article
- Review
- Small Molecule Modulator of the mTORC2 Pathway Discovered from a DEL Library Designed to Bind to Pleckstrin Homology Domains.ACS chemical biology · 2024Article
- Leucyl-tRNA Synthetase Contributes to Muscle Weakness through Mammalian Target of Rapamycin Complex 1 Activation and Autophagy Suppression in a Mouse Model of Duchenne Muscular Dystrophy.The American journal of pathology · 2024Article
- Ligandability at the Membrane Interface of GPx4 Revealed through a Reverse Micelle Fragment Screening Platform.JACS Au · 2024Article
- Ligandability at the membrane interface of GPx4 revealed through a reverse micelle fragment screening platform.bioRxiv : the preprint server for biology · 2024Article
- Lactic acid promotes nucleus pulposus cell senescence and corresponding intervertebral disc degeneration via interacting with Akt.Cellular and molecular life sciences : CMLS · 2024Article
- New drug-like small molecule antagonizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in patients with conotruncal heart defects.Journal of Taibah University Medical Sciences · 2023Article
- Article
- Investigation of the inhibitory behavior of XFE and mitoxantrone molecules in interaction with AKT1 protein: a molecular dynamics simulation study.Journal of molecular modeling · 2023Article
- Suppression of FAM83D Inhibits Glioma Proliferation, Invasion and Migration by Regulating the AKT/mTOR Signaling Pathway.Translational oncology · 2022Article
- Systematic simulation of the interactions of pleckstrin homology domains with membranes.Science advances · 2022Article
- Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein.Critical care (London, England) · 2022Article
- Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Article
- IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms.Journal for immunotherapy of cancer · 2021Article
- Article
- Flufenamic Acid Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells by Antagonizing the PI3K/AKT Signaling Pathway.Stem cells international · 2020Article
- Targeting AKT for cancer therapy.Expert opinion on investigational drugs · 2019Review
- The Akt pathway in oncology therapy and beyond (Review).International journal of oncology · 2018Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Persistently hyperphosphorylated Akt contributes to human oncogenesis and resistance to therapy. Triciribine (TCN) phosphate (TCN-P), the active metabolite of the Akt phosphorylation inhibitor TCN, is in clinical trials, but the mechanism by which TCN-P inhibits Akt phosphorylation is unknown. Here we show that in vitro, TCN-P inhibits neither Akt activity nor the phosphorylation of Akt S473 and T308 by mammalian target of rapamycin or phosphoinositide-dependent kinase 1. However, in intact cells, TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and phosphorylation of Akt. Surface plasmon resonance shows that TCN, but not TCN, binds Akt-derived pleckstrin homology (PH) domain (K(D): 690 nM). Furthermore, nuclear magnetic resonance spectroscopy shows that TCN-P, but not TCN, binds to the PH domain in the vicinity of the PIP3-binding pocket. Finally, constitutively active Akt mutants, Akt1-T308D/S473D and myr-Akt1, but not the transforming mutant Akt1-E17K, are resistant to TCN and rescue from its inhibition of proliferation and induction of apoptosis. Thus, the results of our studies indicate that TCN-P binds to the PH domain of Akt and blocks its recruitment to the membrane, and that the subsequent inhibition of Akt phosphorylation contributes to TCN-P antiproliferative and proapoptotic activities, suggesting that this drug may be beneficial to patients whose tumors express persistently phosphorylated Akt.
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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.