ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2020
Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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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.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.Aging and disease · 2026Article
- An evolutionarily conserved salt bridge stabilizes the active site for GTP hydrolysis in Rho GTPases.The Journal of biological chemistry · 2026Article
- Mechanism of SC targeting RhoA regulation and its potential value in gastric cancer therapy.Biochemistry and biophysics reports · 2025Article
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- Synthesis and in vitro evaluation of benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives as anticancer agents targeting the RhoA/ROCK pathway.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex.Nature communications · 2024Article
- Assessing the mechanism of fast-cycling cancer-associated mutations of Rac1 small Rho GTPase.Protein science : a publication of the Protein Society · 2024Article
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- RHO GTPase family in hepatocellular carcinoma.Experimental hematology & oncology · 2022Review
- Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease.Cells · 2022Article
- Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein.Angewandte Chemie (International ed. in English) · 2021Article
- Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3.Acta pharmaceutica Sinica. B · 2021Article
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- Progress in the therapeutic inhibition of Cdc42 signalling.Biochemical Society transactions · 2021Review
- Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
Corrections and comments
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Authors and funding
26 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well-characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well-conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC-Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC-Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC-Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti-metastasis drug development, and also provides a novel strategy for inhibitor discovery toward "undruggable" protein targets.
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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.