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.
Tian
S S
SS
Department of Transcription Research, Ligand Pharmaceuticals, San Diego, CA 92121, USA.
Lamb
P
P
King
A G
AG
Miller
S G
SG
Kessler
L
L
Luengo
J I
JI
Averill
L
L
Johnson
R K
RK
Gleason
J G
JG
Pelus
L M
LM
Dillon
S B
SB
Rosen
J
J
D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007958:Leukocyte Count; D019891:Leukopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D009504:Neutrophils / Q000166:cytology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D006146:Guanidines; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; C113274:SB 247464; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2