ArticleProceedings of the National Academy of Sciences of the United States of America2013
Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility.
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 109 papers.
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Who cites it
109 citing papers in PubMed, 175 citations in OpenAlex.
- A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients.Clinical cancer research : an official journal of the American Association for Cancer Research · 2015Trial
- Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities.Biochemical Society transactions · 2026Review
- Stalling the Enemy: Targeting Nsp13 for Next-Generation SARS-CoV-2 Antivirals.International journal of molecular sciences · 2026Article
- Leukocyte-epithelial physical contacts mediate interstitial migration in vivo.Research square · 2026Article
- Targeting Cdc42: Novel Approaches in Cardiovascular Disorders.Current protein & peptide science · 2026Review
- Targeting CDC42 Protects Mitochondrial Function through KLF2/HIF-1α/PINK1 Signaling in Acute Kidney Injury.International journal of biological sciences · 2026Article
- Rho Small GTPase Family in Androgen-Regulated Prostate Cancer Progression and Metastasis.Cancers · 2025Review
- Intersectin1/cdc42 signaling regulates methamphetamine-induced neuronal remodeling in the hippocampus.Cellular and molecular life sciences : CMLS · 2025Article
- Constructive Neuroengineering of Axon Polarization Control Using Modifiable Agarose Gel Platforms for Neuronal Circuit Construction.Gels (Basel, Switzerland) · 2025Article
- Migrating immune cells globally coordinate protrusive forces.Nature immunology · 2025Article
- Methods for Controlling Small GTPase Activity.Chembiochem : a European journal of chemical biology · 2025Review
- Emerging mechanomedicines informed by mechanotransduction along the integrin-cytoskeleton-nucleus axis.APL bioengineering · 2025Review
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- Traveling-wave chemotaxis of neutrophil-like HL-60 cells.Molecular biology of the cell · 2025Article
- pERK transition-induced directional mode switching promotes epithelial tumor cell migration.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators.Communications chemistry · 2024Article
- RhoJ: an emerging biomarker and target in cancer research and treatment.Cancer gene therapy · 2024Review
- Estrogen inhibits TGF‑β1‑stimulated cardiac fibroblast differentiation and collagen synthesis by promoting Cdc42.Molecular medicine reports · 2024Article
- Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.Journal of medicinal chemistry · 2024Article
- A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3β/β-catenin Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
49 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Signaling through the Rho family of small GTPases has been intensely investigated for its crucial roles in a wide variety of human diseases. Although RhoA and Rac1 signaling pathways are frequently exploited with the aid of effective small molecule modulators, studies of the Cdc42 subclass have lagged because of a lack of such means. We have applied high-throughput in silico screening and identified compounds that are able to fit into the surface groove of Cdc42, which is critical for guanine nucleotide exchange factor binding. Based on the interaction between Cdc42 and intersectin (ITSN), a specific Cdc42 guanine nucleotide exchange factor, we discovered compounds that rendered ITSN-like interactions in the binding pocket. By using in vitro binding and imaging as well as biochemical and cell-based assays, we demonstrated that ZCL278 has emerged as a selective Cdc42 small molecule modulator that directly binds to Cdc42 and inhibits its functions. In Swiss 3T3 fibroblast cultures, ZCL278 abolished microspike formation and disrupted GM130-docked Golgi structures, two of the most prominent Cdc42-mediated subcellular events. ZCL278 reduces the perinuclear accumulation of active Cdc42 in contrast to NSC23766, a selective Rac inhibitor. ZCL278 suppresses Cdc42-mediated neuronal branching and growth cone dynamics as well as actin-based motility and migration in a metastatic prostate cancer cell line (i.e., PC-3) without disrupting cell viability. Thus, ZCL278 is a small molecule that specifically targets Cdc42-ITSN interaction and inhibits Cdc42-mediated cellular processes, thus providing a powerful tool for research of Cdc42 subclass of Rho GTPases in human pathogenesis, such as those of cancer and neurological disorders.
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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.