ArticleInternational journal of molecular sciences2023
Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma.
Article in International journal of molecular sciences, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Chemical Bond-Orchestrated Energy Depletion to Augment Lung Cancer Chemo-Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Phosphoinositide-dependent kinase 1 (PDK1) in cancer: molecular insights and therapeutic strategies.Frontiers in chemistry · 2026Review
- Optical and Computational Studies on a Triazine Derivative of Dual Fluorescence Enhancement/Superquenching Upon Nanoparticle Interactions.Journal of fluorescence · 2026Article
- Herbal Composition Inhibits Mitochondrial Oxidative Phosphorylation to Prevent HER2-Positive Breast Cancer and Identifies Potential Active Compounds.International journal of molecular sciences · 2025Article
- Novel Pyrazolo [1,5-a]-1,3,5-Triazine Derivatives as CDK7 Inhibitors: Synthesis and Biological Insights in Pancreatic Ductal Adenocarcinoma Models.ChemMedChem · 2025Article
- New Marine-Inspired Oxadiazole Derivatives for Use Against Pancreatic Ductal Adenocarcinoma.Marine drugs · 2025Article
- Article
- Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry.Annals of medicine · 2024Article
- Review
- Evaluation of Helium Ion Radiotherapy in Combination with Gemcitabine in Pancreatic Cancer In Vitro.Cancers · 2024Article
- Circ_0002395 promotes aerobic glycolysis and proliferation in pancreatic adenocarcinoma cells via miR-548c-3p/PDK1 axis.Journal of bioenergetics and biomembranes · 2024Article
- MarineMarine drugs · 2024Review
- Identification of Biomarkers Associated with Oxidative Stress and Immune Cells in Acute Pancreatitis.Journal of inflammation research · 2024Article
- AHNAK2 Promotes the Progression of Pancreatic Ductal Adenocarcinoma by Maintaining the Stability of c-MET.Cancer management and research · 2024Article
- Nortopsentins as Leads from Marine Organisms for Anticancer and Anti-Inflammatory Agent Development.Molecules (Basel, Switzerland) · 2023Review
- Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants.International journal of molecular sciences · 2023Article
- 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1.Marine drugs · 2023Article
- Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound
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Registered trials
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