A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor [see commetns].

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.

[1]  H. Anaguchi,et al.  Evidence for the ligand‐induced conversion from a dimer to a tetramer of the granulocyte colony‐stimulating factor receptor , 1994, FEBS letters.

[2]  P. Lamb,et al.  Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes. , 1996, Blood.

[3]  S. Nagata,et al.  Functional domains of the granulocyte colony‐stimulating factor receptor. , 1991, The EMBO journal.

[4]  Ronald W. Barrett,et al.  Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin , 1996, Science.

[5]  J. Darnell,et al.  Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. , 1994, Science.

[6]  P. Lamb,et al.  Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor , 1994 .

[7]  T. Arakawa,et al.  Dimerization of the extracellular domain of granuloycte-colony stimulating factor receptor by ligand binding: a monovalent ligand induces 2:2 complexes. , 1996, Biochemistry.

[8]  S. Chevalier,et al.  gp130 Transducing Receptor Cross-linking Is Sufficient to Induce Interleukin-6 Type Responses (*) , 1996, The Journal of Biological Chemistry.

[9]  J. Darnell,et al.  Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.

[11]  G. Demetri,et al.  Granulocyte colony-stimulating factor and its receptor. , 1991, Blood.

[12]  O. Silvennoinen,et al.  Signaling through the hematopoietic cytokine receptors. , 1995, Annual review of immunology.

[13]  N. Nicola,et al.  Proliferative effects of purified granulocyte colony‐stimulating factor (G‐CSF) on normal mouse hemopoietic cells , 1983, Journal of cellular physiology.

[14]  Ivan Damjanov,et al.  Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line , 1979, Nature.

[15]  S. Nagata,et al.  Expression cloning of a receptor for murine granulocyte colony-stimulating factor , 1990, Cell.

[16]  C. Heldin,et al.  Dimerization of cell surface receptors in signal transduction , 1995, Cell.

[17]  H. Fujita,et al.  Establishment and characterization of an erythropoietin-dependent subline, UT-7/Epo, derived from human leukemia cell line, UT-7. , 1993, Blood.