Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

Planesas, Jesús M.; Pérez‐Nueno, Violeta I.; Borrell, José I.; Teixidó, Jordi

doi:10.1016/j.jmgm.2015.05.004

Cited by 17 publications

(7 citation statements)

References 81 publications

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“…It should be stressed however that some of the CXCR4 residues identified to bind ligands herein (Fig. 11) were not only reported previously as crucial for binding of small molecules with confirmed allosteric behavior (including our hit compound 7h), but also involved in the chemokine binding [22,27,52]. Therefore, we believe that our compounds bind to different, allosteric pocket, which is partially overlapping with chemokine binding site.…”

Section: Proposed Binding Modes Of Most Potent Negative Allosteric Mo...supporting

confidence: 56%

Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Kolarič

Švajger

Tomašič

et al. 2018

European Journal of Medicinal Chemistry

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Section: Proposed Binding Modes Of Most Potent Negative Allosteric Mo...supporting

confidence: 56%

Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Kolarič

Švajger

Tomašič

et al. 2018

European Journal of Medicinal Chemistry

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“…In the past ten years, a number of inhibitors of CXCL12/CXCR4 which are able to attenuate the growth of tumor cells in vivo and in vitro have been reported We summarize the effects of various CXCR4 inhibitors on tumor in Table 1. So far, CXCR4 antagonists are developed by a number of programs, including five major classes: (1) small modified peptides, including BKT140 [139], FC131 [140–141], T140 [142], POL6326 [143], TF14016 [144]; (2) small-molecules, including the bicyclam AMD070 [145–146], AMD3100 [130, 147–149], AMD11070 [150], MSX-122 [151], GSK812397 [152–153], KRH-3955 [154–155]; (3) antibodies, such as MDX-1338/BMS 93656 [156]; (4) modified agonists and antagonists for CXCL12 such as CTCE-9908 [157–158] ; (5) microRNAs, such as miR-302a [159], miR-9 [160], miR-204-5p[161] and miR-126 [162].…”

Section: Cxcr4 /Cxcl12 Axis As a Therapeutic Target For Cancermentioning

confidence: 99%

Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy

Zhou

Guo

Liu

et al. 2019

CMC

195

143

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Chemokines, which have chemotactic abilities, are comprised of over 50 family members. Through binding to the 7-transmembrane domain of G-protein-coupled receptors (GPCR), they function in immune cells by trafficking and regulating cell prolif¬eration, differentiation, activation, and migration, homing under both physiologic and pathologic conditions. The alpha-chemokine receptor CXCR4 for the alpha-chemokine stromal cell-derived-factor-1 (SDF-1) is most widely expressed by tumors. CXCL12/CXCR4 axis is a major culprit for human tumor because of its crucial role in tumor initiation and progression by activating a number of signaling pathways, such as ERK1/2, ras, PLC/ MAPK, p38 MAPK, and SAPK/ JNK, as well as regulating cancer stem cells. CXCL12/CXCR4 antagonists have been developed, which have shown promising results in both in vitro and in vivo anti-cancer activity in several tumor types. This review provides an evaluation of CXCL12/CXCR4 as a potential therapeutic target for human tumors; it also focuses on the synergistic effects of inhibition of CXCL12/CXCR4 axis and immunotherapy as well as chemotherapy. Together, CXCL12/CXCR4 axis can be a potential therapeutic target for tumors and used with immunotherapy for additive effects.

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“…The peptide sequence of a pepducin is derived from one of the intracellular loops of a target GPCR and is typically connected to palmitic acid or other fatty acids via an amide bond. Pepducins can act as positive or negative allosteric GPCR modulators, and experimental evidence (Covic et al, 2002;Wielders et al, 2007;Janz et al, 2011) and modeling (Planesas et al, 2015) suggest that they bind to an allosteric, intracellular site on the target receptor. Their lipid tail is crucial for activity as it probably anchors the pepducin in the cell membrane (Covic et al, 2002).…”

Section: Pepducinsmentioning

confidence: 99%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

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The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the smallmolecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio-and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENTTo investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.

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Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

Cited by 17 publications

References 81 publications

Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy

Modulators of CXCR4 and CXCR7/ACKR3 Function

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