ArticleProceedings of the National Academy of Sciences of the United States of America2011
Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
38 citing papers in PubMed, 77 citations in OpenAlex.
- Targeting a Pleckstrin Homology Domain with a Lysine-Reactive Covalent Binder.Journal of medicinal chemistry · 2026Article
- New Mechanisms Underlying Oncogenesis in Dbl Family Rho Guanine Nucleotide Exchange Factors.Molecular pharmacology · 2024Review
- LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response.International journal of molecular medicine · 2023Article
- Interfering with the Ubiquitin-Mediated Regulation of Akt as a Strategy for Cancer Treatment.International journal of molecular sciences · 2023Review
- Detecting Förster resonance energy transfer in living cells by conventional and spectral flow cytometry.Cytometry. Part A : the journal of the International Society for Analytical Cytology · 2022Article
- Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges.Molecules (Basel, Switzerland) · 2022Review
- Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth.Cell communication and signaling : CCS · 2022Article
- Extracellular ATP promotes breast cancer chemoresistance via HIF-1α signaling.Cell death & disease · 2022Article
- Utilization of kinase inhibitors as novel therapeutic drug targets: A review.Oncology research · 2022Review
- SC66 inhibits the proliferation and induces apoptosis of human bladder cancer cells by targeting the AKT/β-catenin pathway.Journal of cellular and molecular medicine · 2021Article
- Parental energy-sensing pathways control intergenerational offspring sex determination in the nematode Auanema freiburgensis.BMC biology · 2021Article
- Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The therapeutic value of SC66 in human renal cell carcinoma cells.Cell death & disease · 2020Article
- Discovery of Small Molecules That Target the Phosphatidylinositol (3,4,5) Trisphosphate (PIPMolecular pharmacology · 2020Article
- AKT Inhibitor SC66 Inhibits Proliferation and Induces Apoptosis in Human Glioblastoma Through Down-Regulating AKT/β-Catenin Pathway.Frontiers in pharmacology · 2020Article
- Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells.Cancers · 2019Article
- Quantitative in situ proximity ligation assays examining protein interactions and phosphorylation during smooth muscle contractions.Analytical biochemistry · 2019Article
- Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a NovelCancer discovery · 2019Article
- Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.Cell death & disease · 2019Article
- Targeting Akt by SC66 triggers GSK-3β mediated apoptosis in colon cancer therapy.Cancer cell international · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
The phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase. Following the PIP3-mediated activation at the membrane, the activated Akt is subjected to other regulatory events, including ubiquitination-mediated deactivation. Here, by identifying and characterizing an allosteric inhibitor, SC66, we show that the facilitated ubiquitination effectively terminates Akt signaling. Mechanistically, SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination. A known PH domain-dependent allosteric inhibitor, which stabilizes Akt, prevents the SC66-induced Akt ubiquitination. A cancer-relevant Akt1 (e17k) mutant is unstable, making it intrinsically sensitive to functional inhibition by SC66 in cellular contexts in which the PI3K inhibition has little inhibitory effect. As a result of its dual inhibitory activity, SC66 manifests a more effective growth suppression of transformed cells that contain a high level of Akt signaling, compared with other inhibitors of PIP3/Akt pathway. Finally, we show the anticancer activity of SC66 by using a soft agar assay as well as a mouse xenograft tumor model. In conclusion, in this study, we not only identify a dual-function Akt inhibitor, but also demonstrate that Akt ubiquitination could be chemically exploited to effectively facilitate its deactivation, thus identifying an avenue for pharmacological intervention in Akt signaling.
Indexed as
Identifiers
What OpenQuestion holds
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.