ArticleACS chemical biology2012
A competitive nucleotide binding inhibitor: in vitro characterization of Rab7 GTPase inhibition.
Article in ACS chemical biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 91 citations in OpenAlex.
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- Dysregulation of autophagosome-mitochondria contacts contributes to autophagy dysfunction and neurodegeneration in tauopathy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- SARS-CoV-2 enhances lysosomal exocytosis and deacidifies lysosomes to facilitate viral release.mLife · 2026Article
- Small-molecule inhibitor of Gαo for GNAO1 encephalopathy.Bioscience reports · 2026Article
- Small Molecules to Elevate Rab7-GTPase Activity and Lower Cholesterol Accumulation in Niemann-Pick Type C Disease.Pharmaceutical research · 2026Article
- Methods for Controlling Small GTPase Activity.Chembiochem : a European journal of chemical biology · 2025Review
- AP2A1 activates Rab7 to promote axonal autophagosome transport and slow the progression of Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- Synthesis, antimicrobial evaluation, HPLC-based compound accumulation and docking studies of 2-methoxybenzoyl thioureas.Future medicinal chemistry · 2025Article
- A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer.Cancer research · 2025Article
- Targeting RAB7 in human B lymphoma by a small molecule inhibitor arrests tumor cell growth.Frontiers in oncology · 2025Article
- Intestinal cell diversity and treatment responses in a parasitic nematode at single cell resolution.BMC genomics · 2024Article
- SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle.Nature communications · 2024Article
- Membrane trafficking alterations in breast cancer progression.Frontiers in cell and developmental biology · 2024Review
- Article
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage.Frontiers in immunology · 2023Article
- Lipid droplets as multifunctional organelles related to the mechanism of evasion during mycobacterial infection.Frontiers in cellular and infection microbiology · 2023Review
- Extracellular Hydraulic Resistance Enhances Cell Migration.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.Communications biology · 2022Article
- Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer's Disease.Biomedicines · 2022Review
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Mapping the functionality of GTPases through small molecule inhibitors represents an underexplored area in large part due to the lack of suitable compounds. Here we report on the small chemical molecule 2-(benzoylcarbamothioylamino)-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acid (PubChem CID 1067700) as an inhibitor of nucleotide binding by Ras-related GTPases. The mechanism of action of this pan-GTPase inhibitor was characterized in the context of the Rab7 GTPase as there are no known inhibitors of Rab GTPases. Bead-based flow cytometry established that CID 1067700 has significant inhibitory potency on Rab7 nucleotide binding with nanomolar inhibitor (K(i)) values and an inhibitory response of ≥97% for BODIPY-GTP and BODIPY-GDP binding. Other tested GTPases exhibited significantly lower responses. The compound behaves as a competitive inhibitor of Rab7 nucleotide binding based on both equilibrium binding and dissociation assays. Molecular docking analyses are compatible with CID 1067700 fitting into the nucleotide binding pocket of the GTP-conformer of Rab7. On the GDP-conformer, the molecule has greater solvent exposure and significantly less protein interaction relative to GDP, offering a molecular rationale for the experimental results. Structural features pertinent to CID 1067700 inhibitory activity have been identified through initial structure-activity analyses and identified a molecular scaffold that may serve in the generation of more selective probes for Rab7 and other GTPases. Taken together, our study has identified the first competitive GTPase inhibitor and demonstrated the potential utility of the compound for dissecting the enzymology of the Rab7 GTPase, as well as serving as a model for other small molecular weight GTPase inhibitors.
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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.