A Small, Nonpeptidyl Mimic of Granulocyte-Colony-Stimulating Factor

• Published in: Science (American Association for the Advancement of Science) 1998-07, Vol.281 (5374), p.257-259
• Main Authors: Tian, Shin-Shay, Lamb, Peter, King, Andrew G., Miller, Stephen G., Kessler, Linda, Luengo, Juan I., Averill, Laurie, Johnson, Randall K., Gleason, John G., Pelus, Louis M., Dillon, Susan B., Rosen, Jonathan
• Format: Article
• Language: English
• Subjects: Animals; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzimidazoles - pharmacology; Biological and medical sciences; Cell Line; Cell lines; Cell receptors; Chemistry; Colony-Forming Units Assay; Dimerization; DNA-Binding Proteins - metabolism; Female; Genetics; Granulocyte colony stimulating factor receptors; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - metabolism; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocytes - cytology; Guanidines - chemistry; Guanidines - metabolism; Guanidines - pharmacology; Hep G2 cells; Hormones; Hormones. Endocrine system; Humans; Janus Kinase 1; Janus Kinase 2; Leukocyte Count; Leukopoiesis; Ligand binding (Biochemistry); Ligands; Logical Thinking; Medical sciences; Mice; Mice, Inbred C57BL; Milk Proteins; Molecular biology; Molecules; Neutrophils; Neutrophils - cytology; Organic Chemistry; Pharmacology; Pharmacology. Drug treatments; Phosphorylation; Phosphotyrosine - metabolism; Plasmids; Protein-Tyrosine Kinases - metabolism; Proteins; Proto-Oncogene Proteins; Receptors; Receptors, Granulocyte Colony-Stimulating Factor - chemistry; Receptors, Granulocyte Colony-Stimulating Factor - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Signal Transduction - drug effects; Species Specificity; STAT3 Transcription Factor; STAT5 Transcription Factor; Trans-Activators - metabolism; Transfection; Tumor Cells, Cultured
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.281.5374.257

A nonpeptidyl small molecule SB 247464, capable of activating granulocyte-colony-stimulating factor (G-CSF) signal transduction pathways, was identified in a high-throughput assay in cultured cells. Like G-CSF, SB 247464 induced tyrosine phosphorylation of multiple signaling proteins and stimulated primary murine bone marrow cells to form granulocytic colonies in vitro. It also elevated peripheral blood neutrophil counts in mice. The extracellular domain of the murine G-CSF receptor was required for the activity of SB 247464, suggesting that the compound acts by oligomerizing receptor chains. The results indicate that a small molecule can activate a receptor that normally binds a relatively large protein ligand.