ArticleThe Journal of biological chemistry2015
Combined rational design and a high throughput screening platform for identifying chemical inhibitors of a Ras-activating enzyme.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 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
14 citing papers in PubMed, 31 citations in OpenAlex.
- SOS1: tracking the evolving path from promising to actionable therapeutic target in RAS-dependent cancers.Molecular cancer · 2026Review
- Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.Frontiers in chemistry · 2026Review
- Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis.ACS pharmacology & translational science · 2024Article
- SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6-mediated Axl and RON signaling.The Prostate · 2022Article
- Conformations and binding pockets of HRas and its guanine nucleotide exchange factors complexes in the guanosine triphosphate exchange process.Journal of computational chemistry · 2022Article
- Review
- Targeting the Small GTPase Superfamily through Their Regulatory Proteins.Angewandte Chemie (International ed. in English) · 2020Review
- Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-src Tyrosine Kinase.International journal of molecular sciences · 2019Article
- Ras and Rap1: A tale of two GTPases.Seminars in cancer biology · 2019Review
- How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma.Hepatic oncology · 2018Review
- Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.Chemical Society reviews · 2016Review
- GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site.The Journal of biological chemistry · 2015Article
- Computational exploration of a protein receptor binding space with student proposed peptide ligands.Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular BiologyArticle
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions.
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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.