RESUMEN
The chemokine stromal cell-derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.
Asunto(s)
Adhesión Celular , Supervivencia Celular , Quimiocinas CXC/metabolismo , Neoplasias/inmunología , Receptores CXCR4/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Factor de Transcripción Brn-3A/metabolismo , Animales , Línea Celular , Quimiocina CXCL11 , Quimiocina CXCL12 , Quimiocinas CXC/genética , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Datos de Secuencia Molecular , Neoplasias/patología , Embarazo , Unión Proteica , Receptores CXCR , Receptores CXCR4/genética , Receptores Acoplados a Proteínas G/genética , Factor de Transcripción Brn-3A/genéticaRESUMEN
A series of 2-aminothiazole-derived antagonists of the CCR4 receptor has been synthesized and their affinity for the receptor evaluated using a [(125)I]TARC (CCL17) displacement assay. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent, orally bioavailable antagonists.
