ArticleThe Journal of biological chemistry2011
Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 66 citations in OpenAlex.
- Phosphoinositide-dependent kinase 1 (PDK1) in cancer: molecular insights and therapeutic strategies.Frontiers in chemistry · 2026Review
- Kinase signaling cascades: an updated mechanistic landscape.Chemical science · 2025Review
- Small molecule inhibitors for treating breast cancer: drug analysis based on the pathogenesis of breast cancer.Future medicinal chemistry · 2025Review
- 3-Phosphoinositide-Dependent Kinase 1 as a Therapeutic Target for Treating Diabetes.Current diabetes reviews · 2025Review
- CAP superfamily proteins in human: a new target for cancer therapy.Medical oncology (Northwood, London, England) · 2024Review
- Capturing Autoinhibited PDK1 Reveals the Linker's Regulatory Role, Informing Innovative Inhibitor Design.Journal of chemical information and modeling · 2024Article
- A Genome-Wide Screen Identifies PDPK1 as a Target to Enhance the Efficacy of MEK1/2 Inhibitors in NRAS Mutant Melanoma.Cancer research · 2022Article
- The Landscape of PDK1 in Breast Cancer.Cancers · 2022Review
- Article
- The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1.Journal of enzyme inhibition and medicinal chemistry · 2019Review
- Preclinical validation of 3-phosphoinositide-dependent protein kinase 1 inhibition in pancreatic cancer.Journal of experimental & clinical cancer research : CR · 2019Article
- ProSelection: A Novel Algorithm to Select Proper Protein Structure Subsets for in Silico Target Identification and Drug Discovery Research.Journal of chemical information and modeling · 2017Article
- Targeting PDK1 for Chemosensitization of Cancer Cells.Cancers · 2017Review
- Conditional cell reprogramming involves non-canonical β-catenin activation and mTOR-mediated inactivation of Akt.PloS one · 2017Article
- The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis.Antimicrobial agents and chemotherapy · 2016Article
- Article
- Short-form Ron is a novel determinant of ovarian cancer initiation and progression.Genes & cancer · 2016Article
- Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase.ACS infectious diseases · 2016Article
- Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts.Biochemical and biophysical research communications · 2016Article
- Involvement of multiple cellular pathways in regulating resistance to tamoxifen in BIK-suppressed MCF-7 cells.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
Corrections and comments
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Authors and funding
29 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.
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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.