Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

Verzijl, Dennis; Leurs, Rob; Esch, Iwan J. P. de; Smit, Martine J.

doi:10.1002/cmdc.200700365

Cited by 75 publications

(67 citation statements)

References 106 publications

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“…In general, small-molecule ligands for chemokine receptors are characterized by a positively charged quaternary ammonium and aromatic groups around it (Wijtmans et al, 2008). This positive charge often contributes significantly to the affinity of the ligand, as observed for the biaryl-and piperazinylpiperidine class of CXCR3 ligands Wijtmans et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of the CXCR3 receptor and/or its ligands (CXCL9, CXCL10, CXCL11) is often observed in rheumatoid arthritis and transplant rejection (Lacotte et al, 2009). In the past decade, many efforts have focused on the discovery of small molecule CXCR3 antagonists, leading to the disclosure of ligands with a multitude of different chemotypes (Wijtmans et al, 2008(Wijtmans et al, , 2010 …”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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

Self Cite

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“…Therefore, we tested whether blockade of CXCR3 by AMG487, a potent and orally bioavailable CXCR3 antagonist, 47 Figure S8), food/water consumption and feces, breathing/behavior, and hunching, indicating that vehicle treatment is neither toxic to mice nor to the retina. Similarly, AMG487 treatment did not show adverse effects, such as change in body weight ( Figure 5A), food/water consumption and feces, breathing/behavior, and hunching.…”

Section: Pharmacological Blockade Of Cxcr3 Partially Prevents Rgc Dysmentioning

confidence: 99%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death. (Am J Pathol 2017, 187: 352e365; http://dx

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“…Antagonising CXCR3-dependent pathways has been shown to have therapeutical effects in different diseases (e.g. cardiovascular disorders, cancer) [65][66][67]. However, due to insufficient efficacy, some of the antagonists had to be withdrawn from active trials, and new antagonists are currently being developed [65].…”

Section: Cxcl9 Cxcl10 Cxcl11 and Their Common Receptor Cxcr3mentioning

confidence: 99%

The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact

2009

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International audienceChemokines are centrally involved in leukocyte migration, homing and haematopoiesis. Besides these physiological aspects, their role in pathological processes especially with respect to solid tumour and haematological neoplasias is well established. In this context, the focus was set here on disclosing their contribution in B cell chronic lymphocytic leukaemia (B-CLL), which is regarded as the most characteristic low-grade lymphoma. Up to now, it has been demonstrated that several chemokines are involved in migration of B-CLL cells to lymph nodes, secondary lymphoid organs and bone marrow. Moreover, some chemokines are known to have an anti-apoptotic effect and thus contribute to the survival of B-CLL cells. By interfering with both of these aspects, new therapeutic targets for this yet incurable disease may be developed. Furthermore, a correlation can be drawn between the concentration of some chemokines in patients' serum, the expression of their respective receptors on B-CLL cells and well-established predictive clinical parameters. Consequently, further systematic investigation of the chemokine network may lead to the identification of new diagnostic and prognostic markers. This review focuses on the impact of chemokines and their receptors on B-CLL pathophysiology and points out potential implications for both treatment and diagnosis

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Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

Cited by 75 publications

References 106 publications

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

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

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact

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