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Originally published In Press as doi:10.1074/jbc.M209220200 on January 10, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9426-9434, March 14, 2003
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Selective Binding and Oligomerization of the Murine Granulocyte Colony-stimulating Factor Receptor by a Low Molecular Weight, Nonpeptidyl Ligand*

Michael L. Doyleab, Shin-Shay Tiancd, Stephen G. Millere, Linda Kesslerc, Audrey E. Bakera, Michael R. Brigham-Burkea, Susan B. Dillonfg, Kevin J. Duffyh, Richard M. Keenanh, Ruth Lehri, Jon Rosene, Lumelle A. Schneeweisa, John Trillj, Peter R. Youngjk, Juan I. Luengoh, and Peter Lambcl

From the Departments of h Medicinal Chemistry and f Molecular Virology and Host Defence, GlaxoSmithKline, Collegeville, Pennsylvania 19426, a Structural Biology, i Protein Biochemistry, and j Gene Expression Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, and the Departments of e New Leads Discovery and c Transcription Research, Ligand Pharmaceuticals, San Diego, California 92121

Granulocyte colony-stimulating factor regulates neutrophil production by binding to a specific receptor, the granulocyte colony-stimulating factor receptor, expressed on cells of the granulocytic lineage. Recombinant forms of granulocyte colony-stimulating factor are used clinically to treat neutropenias. As part of an effort to develop granulocyte colony-stimulating factor mimics with the potential for oral bioavailability, we previously identified a nonpeptidyl small molecule (SB-247464) that selectively activates murine granulocyte colony-stimulating factor signal transduction pathways and promotes neutrophil formation in vivo. To elucidate the mechanism of action of SB-247464, a series of cell-based and biochemical assays were performed. The activity of SB-247464 is strictly dependent on the presence of zinc ions. Titration microcalorimetry experiments using a soluble murine granulocyte colony-stimulating factor receptor construct show that SB-247464 binds to the extracellular domain of the receptor in a zinc ion-dependent manner. Analytical ultracentrifugation studies demonstrate that SB-247464 induces self-association of the N-terminal three-domain fragment in a manner that is consistent with dimerization. SB-247464 induces internalization of granulocyte colony-stimulating factor receptor on intact cells, consistent with a mechanism involving receptor oligomerization. These data show that small nonpeptidyl compounds are capable of selectively binding and inducing productive oligomerization of cytokine receptors.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b Present address: Bristol Myers Squibb PRI, Princeton, NJ 08543.

d Present address: Deltagene, 4570 Executive Dr., San Diego, CA 92121.

g Present address: Centocor, 200 Great Valley Pkwy., Malvern, PA 19355.

k Present address: Sugen Inc., 230 E. Grand Ave., South San Francisco, CA 94080.

l To whom correspondence should be addressed: Exelixis Inc., 170 Harbor Way, South San Francisco, CA 94080. Tel.: 650-837-7064; Fax: 650-837-8181; E-mail: plamb@exelixis.com.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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