Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists

Wijtmans, Maikel; Maussang, David; Sirci, Francesco; Scholten, Danny J.; Canals, Meritxell; Mujić-Delić, Azra; Chong, Milagros; Chatalic, Kristell L.S.; Custers, Hans; Janssen, Elwin; Graaf, Chris de; Smit, Martine J.; Esch, Iwan J. P. de; Leurs, Rob

doi:10.1016/j.ejmech.2012.02.041

Cited by 57 publications

(83 citation statements)

References 24 publications

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“…CXCR7 (4,9,26). Thus, we evaluated whether the CXCR7-targeted Nanobodies would behave as CXCR7 agonists or act as antagonists in a ␤-arrestin2 recruitment assay.…”

Section: Resultsmentioning

confidence: 99%

“…To functionally characterize these Nanobodies, we used a ␤-arrestin2 BRET recruitment assay, as CXCR7 is devoid of the classical G protein-mediated signaling (4). Interestingly, unlike our CXCR7-specific small molecule VUF11403 (26), the majority of Nanobodies act as antagonists on CXCR7 and do not induce recruitment of ␤-arrestin (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

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Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

Maussang

Mujić-Delić

Descamps

et al. 2013

Journal of Biological Chemistry

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126

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Background:The atypical chemokine receptor CXCR7 is highly expressed in various types of cancer. Results: CXCR7 Nanobodies were generated and show inhibition of ␤-arrestin2 signaling and secretion of angiogenic CXCL1 in vitro. Anti-CXCR7 Nanobodies reduce tumor growth by inhibiting angiogenesis. Conclusion: CXCR7 inhibition by Nanobodies inhibit head and neck tumor formation. Significance: Anti-CXCR7 therapies are potential novel treatments against head and neck cancer.

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“…CXCR7 (4,9,26). Thus, we evaluated whether the CXCR7-targeted Nanobodies would behave as CXCR7 agonists or act as antagonists in a ␤-arrestin2 recruitment assay.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

Maussang

Mujić-Delić

Descamps

et al. 2013

Journal of Biological Chemistry

Self Cite

126

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“…However, these detailed structures are currently not available. At present, a limited number of CXCR7 ligands have been reported (Kalatskaya et al, 2009; Gravel et al, 2010; Wijtmans et al, 2012), therefore the application of GPCR homology modeling and virtual screening, previously used in CXCR4 studies, for novel CXCR7 ligand identification represents a promising tool (Yoshikawa et al, 2013). AMD3100 and the peptidomimetic CXCR4 antagonist TC14012 have also been reported to act as partial CXCR7 agonists (Kalatskaya et al, 2009; Gravel et al, 2010).…”

Section: Targeting Cxcl12–cxcr4/cxcr7 Axis In Cancer: Rationalementioning

confidence: 99%

“…Several pharmacological studies with small-molecule CXCR7 antagonists endowed with reasonable affinities have been reported, but none disclosed a structure for the antagonists (Burns et al, 2006; Zabel et al, 2009; Hattermann et al, 2010; Rajagopal et al, 2010; Cruz-Orengo et al, 2011). A recent paper describes the first reported combined synthetic, modeling and pharmacological effort on small molecules targeting CXCR7 (Wijtmans et al, 2012). …”

Section: Targeting Cxcl12–cxcr4/cxcr7 Axis In Cancer: Rationalementioning

confidence: 99%

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Würth

Bajetto

Harrison

et al. 2014

Front. Cell. Neurosci.

112

128

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Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4–CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.

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“…We were able to identify molecular features that are positively or negatively correlated with the ability of ligands to induce biased hH 4 R signalling. The current study is one of the first to use computational analysis (Sirci et al ., ; Wijtmans et al ., ) to correlate ligand structures with intrinsic activities. Moreover, with a hH 4 R homology model, we could identify receptor regions important for biased hH 4 R signalling.…”

Section: Introductionmentioning

confidence: 99%

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

Nijmeijer¹,

Vischer²,

Sirci

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEThe histamine H4 receptor, originally thought to signal merely through Gai proteins, has recently been shown to also recruit and signal via b-arrestin2. Following the discovery that the reference antagonist indolecarboxamide JNJ 7777120 appears to be a partial agonist in b-arrestin2 recruitment, we have identified additional biased hH4R ligands that preferentially couple to Gai or b-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH4R signalling. EXPERIMENTAL APPROACHWe evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH4R-mediated Gai protein signalling or b-arrestin2 recruitment. Subsequently, a Fingerprints for Ligands and Proteins three-dimensional quantitative structure-activity relationship analysis correlated intrinsic activity values with structural ligand requirements. Moreover, a hH4R homology model was used to identify receptor regions important for biased hH4R signalling. KEY RESULTSOne indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Gai and b-arrestin2 pathway and was classified as unbiased hH4R ligand. The other 47 indolecarboxamides were b-arrestin2-biased agonists. Intrinsic activities of the unbiased as well as b-arrestin2-biased indolecarboxamides to induce b-arrestin2 recruitment could be correlated with different ligand features and hH4R regions. CONCLUSION AND IMPLICATIONSSmall structural modifications resulted in diverse intrinsic activities for unbiased (75) and b-arrestin2-biased indolecarboxamides. Analysis of ligand and receptor features revealed efficacy hotspots responsible for biased-b-arrestin2 recruitment. This knowledge is useful for the design of hH4R ligands with biased intrinsic activities and aids our understanding of the mechanism of H4R activation.

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Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists

Cited by 57 publications

References 24 publications

Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

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Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists

Cited by 57 publications

References 24 publications

Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues

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Product

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Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues