ArticleProceedings of the National Academy of Sciences of the United States of America2013
Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 147 citations in OpenAlex.
- Proposal of Chemical Inhibitors That Compete with the Binding of RNA Polymerase II Subunits to Essential GTPases GPN Npa3 and Gpn1.ACS omega · 2025Article
- A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1.Nature communications · 2024Article
- Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning.Molecules (Basel, Switzerland) · 2024Article
- Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Alchemical Free Energy Calculations on Membrane-Associated Proteins.Journal of chemical theory and computation · 2023Review
- Discovery of Hit Compounds Targeting the P4 Allosteric Site of K-RAS, Identified through Ensemble-Based Virtual Screening.Journal of chemical information and modeling · 2023Article
- Andropanilides A-C, the novel labdane-type diterpenoids from Andrographis paniculata and their anti-inflammation activity.Natural products and bioprospecting · 2023Article
- Article
- Andrographolide suppresses aerobic glycolysis and induces apoptotic cell death by inhibiting pyruvate dehydrogenase kinase 1 expression.Oncology reports · 2023Article
- Eliminating oncogenic RAS: back to the future at the drawing board.Biochemical Society transactions · 2023Article
- KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement.ACS bio & med chem Au · 2022Article
- Computer-Aided Drug Design Boosts RAS Inhibitor Discovery.Molecules (Basel, Switzerland) · 2022Review
- Deciphering Conformational Changes of the GDP-Bound NRAS Induced by Mutations G13D, Q61R, and C118S through Gaussian Accelerated Molecular Dynamic Simulations.Molecules (Basel, Switzerland) · 2022Article
- Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations.Physical chemistry chemical physics : PCCP · 2022Article
- Novel STAT3 small-molecule inhibitors identified by structure-based virtual ligand screening incorporating SH2 domain flexibility.Pharmacological research · 2021Article
- Approaches to inhibiting oncogenic K-Ras.Small GTPases · 2021Review
- Molecular Dynamics Simulation of Lipid-Modified Signaling Proteins.Methods in molecular biology (Clifton, N.J.) · 2021Article
- The Adroitness of Andrographolide as a Natural Weapon Against Colorectal Cancer.Frontiers in pharmacology · 2021Review
- Big data and artificial intelligence discover novel drugs targeting proteins without 3D structure and overcome the undruggable targets.Stroke and vascular neurology · 2020Review
- Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives.Biomolecules · 2020Review
1 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)--a bicyclic diterpenoid lactone isolated from Andrographis paniculata--and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.
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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.