Small Molecule CXCR3 Antagonists

Andrews, Stephen P.; Cox, Rhona J.

doi:10.1021/acs.jmedchem.5b01337

Cited by 54 publications

(55 citation statements)

References 144 publications

(222 reference statements)

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“…31 Compound b was further modified to JN-2 (compound c), which contains an amide side chain to mimic the well-known CXCR3 antagonist AMG 487 (compound d), a small molecular antagonist that has been evaluated in Phase IIa clinical trials. 32 …”

Section: Resultsmentioning

confidence: 99%

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

Jin

Kim

et al. 2017

Exp Mol Med

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The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2. In this study, we observed that secretion of CXCL10 in the supernatant of 4T1 cells was gradually increased during cell growth. JN-2 inhibited basal and CXCL10-induced CXCL10 expression and cell motility in 4T1 cells. Treatment of 4T1 cells with CXCL10 increased the expression of P65, a subunit of the NF-κB pathway, via activation of the NF-κB transcriptional activity. Ectopic overexpression of P65 increased CXCL10 secretion and blunted JN-2-induced suppression of CXCL10 secretion, whereas overexpression of IκBα suppressed CXCL10 secretion. These results indicate that the CXCL10/CXCR3 axis creates a positive feedback loop through the canonical NF-κB signaling pathway in 4T1 cells. In addition, treatment of osteoblasts with conditioned medium from JN-2-treated 4T1 cells inhibited the expression of RANKL, a crucial cytokine for osteoclast differentiation, which resulted in an inhibitory effect on osteoclast differentiation in the co-culture system of bone marrow-derived macrophages and osteoblasts. Direct intrafemoral injection of 4T1 cells induced severe bone destruction; however, this effect was suppressed by the CXCR3 antagonist via downregulation of P65 expression in an animal model. Collectively, these results suggest that the CXCL10/CXCR3-mediated NF-κB signaling pathway plays a role in the control of autonomous regulation of CXCL10 and malignant tumor properties in breast cancer 4T1 cells.

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Section: Resultsmentioning

confidence: 99%

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

Jin

Kim

et al. 2017

Exp Mol Med

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“…Nonetheless, if future studies provide mechanistic support for a protumorigenic role of CXCR3 signaling in neurofibroma development, further exploration of CXCR3-targeted neurofibroma prophylaxis may be warranted. Small-molecule inhibitors of CXCR3 are an active area of drug development, with no serious adverse events reported in a phase I clinical trial of the CXCR3 inhibitor AMG-487 (67).…”

Section: Discussionmentioning

confidence: 99%

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Fletcher

Jessen

et al. 2019

JCI Insight

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macrophage subpopulations with distinct activities (24,25). Further characterization of these neurofibroma leukocytes and their contributions to tumor initiation and growth is necessary for the development of safe and effective immunomodulatory therapies.In the Dhh-Cre Nf1 fl/fl mouse neurofibroma model, biallelic deletion of Nf1 in the Schwann cell lineage mimics the biallelic loss of NF1 in human NF1 and sporadic plexiform neurofibroma (26). The peripheral nerves of these mice appear normal at 1 month of age, but pathological changes, including mast cell and macrophage infiltration and abnormal Schwann cell proliferation, are evident at 2 months of age (26,27). By 4 months of age, these mice invariably form MRI-detectable paraspinal neurofibromas that histologically and transcriptionally resemble human plexiform neurofibroma (26,28,29). Schwann cell-specific deletion of Nf1 using other drivers can also induce nerve pathology and neurofibroma development in mice (19,(30)(31)(32). In contrast, CNPase-human EGFR (CNPase-hEGFR) mice have increased Ras activity driven by overexpression of hEGFR and develop similar nerve pathology to Nf1 mouse models but have reduced myeloid cell infiltration, and only approximately 1 in 20 develop a neurofibroma (20,33).Here, we compare nerves from these mouse models transcriptionally and identify a chemokine, Cxcl10, that is uniquely overexpressed in 2-month Dhh-Cre Nf1 fl/fl nerves. CXCL10 and its receptor, CXCR3, are important modulators of neuroinflammation and tumor biology (34)(35)(36). In this study, we identify Cxcl10and Cxcr3-expressing cell populations in nerves and neurofibroma and demonstrate the necessity of Cxcr3 for neurofibroma development in Dhh-Cre Nf1 fl/fl mice. Results Differential gene expression analyses identify Cxcl10 as a potential modulator of plexiform neurofibroma development.Peripheral nerves from GEMMs of NF1 (GEMM-NF1) (P0-CreB Nf1 fl/fl , P0-CreB Nf1 fl/-, Dhh-Cre Nf1 fl/fl ) invariably develop neurofibromas (26,31). P0-CreB and Dhh-Cre are transgenic mouse strains that express Cre recombinase in peripheral nerve Schwann cells; when used to recombine Nf1 in mice, peripheral nerves show pathological mast cell recruitment, disruption of axon and nonmyelinating Schwann cell (axon/ Remak bundle) interactions, and collagen deposition (nerve disruption). This nerve disruption phenotype precedes plexiform neurofibroma development. Although several of these changes have been proposed to contribute to neurofibroma development, similar nerve pathology is also observed in CNPase-hEGFR/ + and CNPase-hEGFR/CNPase-hEGFR mice, which recruit fewer macrophages and rarely form neurofibromas (33,37). In contrast, this pathology is not observed in Npcis mice (Nf1 +/− Trp53 +/− deletions in cis) that progress directly to malignant peripheral nerve sheath tumor (ref. 38 and Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.98601DS1) or in CNPase-HRas12V mice that do not develop plexiform neurofibroma (39)....

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“…Recent studies demonstrated that therapy with potent smallmolecule CXCR3 antagonists showed significant efficacy in animal models of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and in the prevention of transplant rejection. 3,[17][18][19] Cleavage of the transmembrane chemokines CXCL16 and CX3CL1 is associated with the inflammatory cascade and, therefore, the soluble form of the molecules may serve as inflammatory markers.…”

Section: Discussionmentioning

confidence: 99%

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

El‐Asrar

Berghmans

Al-Obeidan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine the levels of the neutrophil chemoattractants CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8, the T helper 1 chemoattractants CXCL9, CXCL10 and CXCL11, the lymphoid chemokines CXCL12 and CXCL13 and the soluble form of the transmembrane chemokines CXCL16 and CX3CL1, in aqueous humor samples from patients with specific uveitic entities.METHODS. Aqueous humor samples from patients with active uveitis associated with Behçet's disease (n ¼ 13), sarcoidosis (n ¼ 8), HLA-B27-related inflammation (n ¼ 12), Vogt-KoyanagiHarada (VKH) disease (n ¼ 12), and healthy controls (n ¼ 9) were assayed with the use of a multiplex assay.RESULTS. All chemoattractant levels were significantly higher in all patients than in the controls. The levels of all neutrophil chemoattractants and CXCL10, CXCL16, and CX3CL1 were significantly higher in nongranulomatous uveitis (Behçet's disease and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease), whereas the levels of the B cell chemoattractant CXCL13 were significantly higher in granulomatous uveitis than in nongranulomatous uveitis. CXCL13 levels were highest in the patients with VKH disease. CXCL9, CXCL11, and CXCL12 levels did not differ significantly.CONCLUSIONS. Inflammation in nongranulomatous uveitis appears to be driven by neutrophils and T helper 1 lymphocytes, whereas B lymphocytes may contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease.

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Small Molecule CXCR3 Antagonists

Cited by 54 publications

References 144 publications

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

NF-κB signaling regulates cell-autonomous regulation of CXCL10 in breast cancer 4T1 cells

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

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