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Science 10 July 1998:
Vol. 281. no. 5374, pp. 257 - 259
DOI: 10.1126/science.281.5374.257
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Reports

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

Shin-Shay Tian, * Peter Lamb, *dagger Andrew G. King, Stephen G. Miller, Linda Kessler, Juan I. Luengo, Laurie Averill, Randall K. Johnson, John G. Gleason, Louis M. Pelus, Susan B. Dillon, Jonathan Rosen

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.

S.-S. Tian, P. Lamb, L. Kessler, J. Rosen, Department of Transcription Research, Ligand Pharmaceuticals, San Diego, CA 92121, USA. A. G. King, L. Averill, L. M. Pelus, S. B. Dillon, Department of Molecular Virology and Host Defence-US, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426, USA. S. G. Miller, Department of New Leads Discovery, Ligand Pharmaceuticals, San Diego, CA 92121, USA. J. I. Luengo and J. G. Gleason, Department of Medicinal Chemistry-US, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426, USA. R. K. Johnson, Department of Oncology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: plamb{at}ligand.com

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