Hematopoietic growth factors (HGFs) have proved to be clinically successful therapeutics; however, their size (15-70 kDa), conformational instability, susceptibility to proteolytic degradation, poor membrane penetration, antigenicity, high cost of production, and unfavorable pharmacokinetics can make them less than ideal drug candidates. Furthermore, the poor bioavailability of the native proteins requires that they be administered parenterally. It would be advantageous, therefore, to develop small-molecule agonists (and antagonists) of HGF receptors that are equipotent to their polypeptide counterparts but that lack some of the inherent drawbacks of large proteins. The identification and examination of smaller peptides that bind to and activate cytokine receptors may provide a better understanding of ligand-receptor interactions, which could be used to design orally available small-molecule cytokine mimetics rationally. Recent advances in both small-molecule and small-peptide agonists are reviewed here.

Activation of transmembrane receptors by growth factors and cytokines occurs when a ligand binds to a specific domain on the receptor, thereby inducing a conforma-tional change (1) and triggering dimerization or oligomerization of receptor chains. Upon ligand binding, several members of the class I cytokine receptors form homo-dimers, including the erythropoietin receptor (EPOR), thrombopoietin receptor

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

(TPOR), granulocyte colony-stimulating factor receptor (G-CSFR), growth hormone receptor (GHR), and prolactin receptor (PrR) (2). Several studies have been reported that are directed toward discovering the precise details of the dimerization interfaces and the degree to which the unliganded receptors exist as dimers (3-5). The results of these studies have shown structural and functional similarities between the class I cytokine receptors. Studies also have shown that receptor dimerization alone, although necessary for intracellular signaling, is not sufficient to produce signal transduction (6). Until recently, mediation of this complex series of events seemed impossible by a small molecule or peptide; however, recent reports have shown that both small molecules and peptides can bind to and activate homodimeric cytokine receptors by acting as agonists and mimicking the effects of the natural proteins.

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