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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Biesiada, Jacek Papoian, Ruben Shang, Xun Seibel, William L. Evelyn, Chris R. Zheng, Yi Meller, Jaroslaw Tang, Hong Nelson, Sandra Duan, Xin |
| Description | Author Affiliation: Evelyn CR ( From the Division of Experimental Hematology and Cancer Biology.); Biesiada J ( Division of Biomedical Informatics.); Duan X ( From the Division of Experimental Hematology and Cancer Biology.); Tang H ( Division of Immunobiology, and the Drug Discovery Center and.); Shang X ( From the Division of Experimental Hematology and Cancer Biology.); Papoian R ( the Drug Discovery Center and Departments of Neurology and.); Seibel WL ( the Drug Discovery Center and Division of Oncology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229 and.); Nelson S ( the Drug Discovery Center and.); Meller J ( Division of Biomedical Informatics, Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267.); Zheng Y ( From the Division of Experimental Hematology and Cancer Biology, Yi.Zheng@cchmc.org.) |
| 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 20 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-05-15 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Enzyme Inhibitors Ras GTPase-Activating Proteins Antagonists & Inhibitors Ras Guanine Nucleotide Exchange Factors Dose-Response Relationship, Drug Drug Delivery Systems Drug Evaluation, Preclinical Chemistry Pharmacology Proto-Oncogene Proteins P21(ras) Genetics Metabolism Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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