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Pharmacological properties of CXCR7 antagonist (CCX754) used in in vivo experiments. The experiments are shown in Fig. 9. (A) Pharmacokinetic properties of CXCR7 antagonist in mice show a serum half-life (T1/2) of 6 h, bioavailability of 20% (F), and an acceptable liver clearance rate of 30 ml/min/kg (CL). These pharmacokinetic properties are compatible with once a day dosing in mouse animal models. (B) CCX754 inhibits binding of 125I SDF-1 to MCF-7 human breast tumor cells with an IC50 of 5 nM. Error bars represent SEM in both panels.
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fig8: Pharmacological properties of CXCR7 antagonist (CCX754) used in in vivo experiments. The experiments are shown in Fig. 9. (A) Pharmacokinetic properties of CXCR7 antagonist in mice show a serum half-life (T1/2) of 6 h, bioavailability of 20% (F), and an acceptable liver clearance rate of 30 ml/min/kg (CL). These pharmacokinetic properties are compatible with once a day dosing in mouse animal models. (B) CCX754 inhibits binding of 125I SDF-1 to MCF-7 human breast tumor cells with an IC50 of 5 nM. Error bars represent SEM in both panels.

Mentions: The role of CXCR7 on cell survival and adhesion, coupled with the pronounced expression of the receptor on transformed cells and activated endothelial cells, prompted us to examine its role in mammalian models of tumor formation. To this end, we tested the CXCR7 antagonist CCX754 (14), an analogue of CCX451 that has superior in vivo pharmacokinetic properties, in mouse models engrafted with various tumors. CCX754's pharmacokinetic properties permitted once daily dosing (Fig. 8 A), bound to CXCR7 with low nM affinity (Fig. 8 B), and demonstrated high selectivity for CXCR7 over other CXCRs (Table I). Efficacy of CCX754 was evaluated in immunodeficient or syngeneic mice engrafted with either human B lymphoma IM9 (Fig. 9 A), human lung carcinoma A549 (Fig. 9 C), or mouse lung carcinoma LL/2 (Fig. 9 D). Each of these tumors was shown to express CXCR7 by both the signature 125I SDF-1 binding profile and flow cytometric staining with the anti-CXCR7 mAb (unpublished data).

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ - J. Exp. Med. (2006)

Bottom Line: 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).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.

Affiliation: ChemoCentryx, Inc., Mountain View, CA 94043, USA.

ABSTRACT
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.

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