CXCR4 antagonist AMD3100 (plerixafor): From an impurity to a therapeutic agent

Wang, Jingzhe; Tannous, Bakhos A.; Poznansky, Mark C.; Chen, Huabiao

doi:10.1016/j.phrs.2020.105010

Cited by 71 publications

(49 citation statements)

References 178 publications

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“…This effect of IT1t was selective: A second antagonist of CXCR4 is AMD3100 (Plerixafor), which is used clinically as a treatment for leukemia and solid tumors (24). This ligand has an approximately tenfold lower affinity for CXCR4 than IT1t ( Figure 3D) (IC50 of 3.9 × 10 -7 M for AMD3100 (against an EC80 concentration of CXCL12) as compared to 2.6 × 10 -8 M for IT1t).…”

Section: The Effect Of It1t Is Selectivementioning

confidence: 99%

“…Overall, these studies show that CXCR4 is significantly organized as a dimer, and that oligomeric organization increases further with increasing receptor expression. Whilst the CXCR4 small molecule antagonist isothiourea-1t (IT1t) rapidly and reversibly promotes monomerization of the receptor, the clinically employed CXCR4 antagonist AMD3100 (24) was not effective in this regard. We also show that specific mutations altering a predicted dimerization interface in transmembrane domain V identified in the atomic level X-ray structures of Wu et al, (7) are indeed able to limit or almost fully abrogate CXCR4 dimerization, whilst dimerization of a constitutively active mutant of CXCR4 is instead actively promoted by binding of IT1t.…”

Section: Introductionmentioning

confidence: 99%

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Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

Ward

Pediani

Marsango

et al. 2021

Journal of Biological Chemistry

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CXCR4, a member of the family of chemokine-activated G protein-coupled receptors, is widely expressed in immune response cells. It is involved in both cancer development and progression as well as viral infection, notably by HIV-1. A variety of methods, including structural information, have suggested the receptor may exist as a dimer or oligomer. However, the mechanistic details surrounding receptor oligomerization and its potential dynamic regulation remain unclear. Using both biochemical and biophysical means we confirm that CXCR4 can exist as a mixture of monomers, dimers and higher-order oligomers in cell membranes and show that oligomeric structure becomes more complex as receptor expression levels increase. Mutations of CXCR4 residues located at a putative dimerization interface result in monomerization of the receptor. Additionally, binding of the CXCR4 antagonist IT1t— a small, drug-like isothiourea derivative — rapidly destabilizes the oligomeric structure, while AMD3100, another well-characterized CXCR4 antagonist, does not. Although a mutation that regulates constitutive activity of CXCR4 also results in monomerization of the receptor, binding of IT1t to this variant promotes receptor dimerization. These results provide novel insights into the basal organization of CXCR4 and how antagonist ligands of different chemotypes differentially regulate its oligomerization state.

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Section: The Effect Of It1t Is Selectivementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

Ward

Pediani

Marsango

et al. 2021

Journal of Biological Chemistry

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“…The CXCR4 receptor for CXCL12 (also known as stromal cell-derived factor 1, SDF-1) also mediates the recruitment of MDSCs. Neutralization of CXCR4 by antagonists, such as AMD3100, reduces the number of MDSCs and T regs and promotes M2 to M1 macrophage polarization in the TME [126,127]. Moreover, the colony-stimulating factor-1 receptor (CSF-1R) is a tyrosine kinase receptor that, when combined with the receptor, can induce the formation of MDSCs and trafficking to tumor sites.…”

Section: Blockade Of Migrationmentioning

confidence: 99%

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

Wang

Jia

et al. 2020

Cancers

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Myeloid-derived suppressor cells (MDSCs), which are activated under pathological conditions, are a group of heterogeneous immature myeloid cells. MDSCs have potent capacities to support tumor growth via inhibition of the antitumoral immune response and/or the induction of immunosuppressive cells. In addition, multiple studies have demonstrated that MDSCs provide potential therapeutic targets for the elimination of immunosuppressive functions and the inhibition of tumor growth. The combination of targeting MDSCs and other therapeutic approaches has also demonstrated powerful antitumor effects. In this review, we summarize the characteristics of MDSCs in the tumor microenvironment (TME) and current strategies of cancer treatment by targeting MDSCs.

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“…Dysregulation of CXCL12/CXCR4 signaling is associated with numerous pathological conditions, including various types of cancers, chronic inflammatory diseases, cardiovascular diseases, and immunodeficiencies [ 13 , 14 , 15 ]. Therefore, CXCR4 is an attractive target for imaging cancerous lesions and their microenvironment which may have clinical applications towards diagnosis and patient selection for not only targeted therapeutics but immunotherapies as well [ 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Automated Synthesis of Fluorine-18 Labeled CXCR4 Ligand via the Conjugation with Nicotinic Acid N-Hydroxysuccinimide Ester (6-[18F]SFPy)

et al. 2020

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The C-X-C motif chemokine receptor 4 (CXCR4) is a seven-transmembrane G protein-coupled receptor that is overexpressed in numerous diseases, particularly in various cancers and is a powerful chemokine, attracting cells to the bone marrow niche. Therefore, CXCR4 is an attractive target for imaging and therapeutic purposes. The goal of this study is to develop an efficient, reproducible, and straightforward method to prepare a fluorine-18 labeled CXCR4 ligand. 6-[18F]Fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester (6-[18F]FPy-TFP) and nicotinic acid N-hydroxysuccinimide ester (6-[18F]SFPy) have been prepared using ‘fluorination on the Sep-Pak’ method. Conjugation of 6-[18F]SFPy or 6-[18F]FPy-TFP with the alpha-amino group at the N terminus of the protected T140 precursor followed by deprotection, yielded the final product 6-[18F]FPy-T140. The overall radiochemical yields were 6–17% (n = 15, decay-corrected) in a 90-min radiolabeling time with a radiochemical purity >99%. 6-[18F]FPy-T140 exhibited high specific binding and nanomolar affinity for CXCR4 in vitro, indicating that the biological activity of the peptide was preserved. For the first time, [18F]SFPy has been prepared using ‘fluorination on the Sep-Pak’ method that allows rapid automated synthesis of 6-[18F]FPy-T140. In addition to increased synthetic efficiency, this construct binds with CXCR4 in high affinity and may have potential as an in vivo positron emission tomography (PET) imaging agent. This radiosynthesis method should encourage wider use of this PET agent to quantify CXCR4 in both research and clinical settings.

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CXCR4 antagonist AMD3100 (plerixafor): From an impurity to a therapeutic agent

Cited by 71 publications

References 178 publications

Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

Automated Synthesis of Fluorine-18 Labeled CXCR4 Ligand via the Conjugation with Nicotinic Acid N-Hydroxysuccinimide Ester (6-[18F]SFPy)

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