Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Heise, Christopher E.; Pahuja, Anil; Hudson, Sarah; Mistry, Monica S.; Putnam, Amy; Gross, Molly M.; Gottlieb, Peter A.; Wade, Warren S.; Kiankarimi, Mehrak; Schwarz, David; Crowe, Paul D.; Zlotnik, Albert; Alleva, David G.

doi:10.1124/jpet.105.083683

Cited by 72 publications

(95 citation statements)

References 35 publications

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“…These ligands exhibit different binding affinity for the receptor with an order of ITAC Ͼ IP-10 Ͼ Mig (39). Interestingly, the affinity of these chemokines for CXCR3 exhibits an inverse relationship to the amount of chemokine production such that Mig with lowest affinity to CXCR3 shows the highest chemokine production (40). Our studies in this report demonstrate a similar pattern of protein expression of the CXCR3 ligands with the expression order of Mig Ͼ IP-10 Ͼ Ͼ ITAC.…”

Section: Discussionsupporting

confidence: 66%

“…Another approach to reduce hepatic damage is to block the action of CXCR3. Several groups have developed small nonpeptide inhibitors that can bind to and inhibit the function of chemokine receptors in vitro and in vivo (40,55). In this case, NBI-74330 (40) demonstrates the ability to inhibit receptor activation by all three CXCR3 ligands and this series (T487) of CXCR3 antagonists are currently in phase II clinical trials.…”

Section: Discussionmentioning

confidence: 99%

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Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4+ T Cell-Dependent Liver Damage

Cruise

Lukens

Nguyen

et al. 2006

The Journal of Immunology

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Immune-mediated hepatic damage has been demonstrated in the pathogenesis of hepatitis C virus (HCV) and other hepatotrophic infections. Fas/Fas ligand (FasL) interaction plays a critical role in immune-mediated hepatic damage. To understand the molecular mechanism(s) of FasL-mediated liver inflammation, we examined the effect of CD4+ T cells expressing high levels of FasL on the initiation of hepatic damage through analysis of chemokine and chemokine receptor expression in HCV core × TCR (DO11.10) double-transgenic mice. In vivo antigenic stimulation triggers a marked influx of core-expressing Ag-specific CD4+ T cells into the liver of the immunized core+ TCR mice but not their core− TCR littermates. Strikingly, the inflammatory process in the liver of core+ TCR mice was accompanied by a dramatic increase in IFN-inducible protein 10 and monokine induced by IFN-γ production. The intrahepatic lymphocytes were primarily CXCR3-positive and anti-CXCR3 Ab treatment abrogates migration of CXCR3+ lymphocytes into the liver and hepatic damage. Importantly, the blockade of Fas/FasL interaction reduces the expression of IFN-inducible protein 10 and monokine induced by IFN-γ and cellular infiltration into the liver. These findings suggest that activated CD4+ T cells with elevated FasL expression are involved in promoting liver inflammation and hepatic damage through the induction of chemokines.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4+ T Cell-Dependent Liver Damage

Cruise

Lukens

Nguyen

et al. 2006

The Journal of Immunology

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“…To assess whether this migration response was mediated by CXCR7, cells were treated with selective chemokine receptor antagonists. Treatment with the CXCR3 antagonist T487 (29) or the CXCR4 antagonist AMD3100 (30) had no significant effect on migration, however, the CXCR7 antagonist CCX733 had a significant inhibitory effect on migration, whereas a structurally related compound which does not bind CXCR7, CCX704, had none (Fig. 4B).…”

Section: Cxcr7 Recruitment Of β-Arrestin Is Associated With Phosphoerkmentioning

confidence: 98%

β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7

Rajagopal

Kim

Ahn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

522

561

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Ubiquitously expressed seven-transmembrane receptors (7TMRs) classically signal through heterotrimeric G proteins and are commonly referred to as G protein-coupled receptors. It is now recognized that 7TMRs also signal through β-arrestins, which act as versatile adapters controlling receptor signaling, desensitization, and trafficking. Most endogenous receptors appear to signal in a balanced fashion using both β-arrestin and G protein-mediated pathways. Some 7TMRs are thought to be nonsignaling “decoys” because of their inability to activate typical G protein signaling pathways; it has been proposed that these receptors act to scavenge ligands or function as coreceptors. Here we demonstrate that ligand binding to the decoy receptor CXCR7 does not result in activation of signaling pathways typical of G proteins but does activate MAP kinases through β-arrestins in transiently transfected cells. Furthermore, we observe that vascular smooth muscle cells that endogenously express CXCR7 migrate to its ligand interferon-inducible T-cell alpha chemoattractant (ITAC), an effect that is significantly attenuated by treatment with either a CXCR7 antagonist or β-arrestin depletion by siRNA. This example of an endogenous “β-arrestin-biased” 7TMR that signals through β-arrestin in the absence of G protein activation demonstrates that some 7TMRs encoded in the genome have evolved to signal through β-arrestin exclusively and suggests that other receptors that are currently thought to be orphans or decoys may also signal through such nonclassical pathways.

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“…shown to bind CXCR3 with nanomolar affinities (Heise et al, 2005;Johnson et al, 2007;Verzijl et al, 2008), and are effective in animal models of disease (Walser et al, 2006;van Wanrooij et al, 2008). AMG487 was even assessed in clinical trials for treatment of psoriasis, but was discontinued after a phase IIa trial ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

Scholten¹,

Roumen²,

Verkade-Vreeker³

et al. 2013

Mol Pharmacol

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CXC chemokine receptor CXCR3 and/or its main three ligands CXCL9, CXCL10, and CXCL11 are highly upregulated in a variety of diseases. As such, considerable efforts have been made to develop small-molecule receptor CXCR3 antagonists, yielding distinct chemical classes of antagonists blocking binding and/or function of CXCR3 chemokines. Although it is suggested that these compounds bind in an allosteric fashion, thus far no evidence has been provided regarding the molecular details of their interaction with CXCR3. Using site-directed mutagenesis complemented with in silico homology modeling, we report the binding modes of two high-affinity CXCR3 antagonists of distinct chemotypes: Here we show that NBI-74330 is anchored in the transmembrane minor pocket lined by helices 2 (W2.60, D2.63), 3 (F3.32), and 7 (S7.39, Y7.43), whereas VUF11211 extends from the minor pocket into the major pocket of the transmembrane domains, located between residues in helices 1 (Y1.39), 2 (W2.60), 3 (F3.32), 4 (D4.60), 6 (Y6.51), and 7 (S7.39, Y7.43). Mutation of these residues did not affect CXCL11 binding significantly, confirming the allosteric nature of the interaction of these small molecules with CXCR3. Moreover, the model derived from our in silico-guided studies fits well with the already published structure-activity relationship data on these ligands. Altogether, in this study, we show overlapping, yet different binding sites for two high-affinity CXCR3 antagonists, which offer new opportunities for the structure-based design of allosteric modulators for CXCR3.

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Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist

Cited by 72 publications

References 35 publications

Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4+ T Cell-Dependent Liver Damage

Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4+ T Cell-Dependent Liver Damage

β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

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