Plerixafor(AMD3100) is a small molecule inhibitor of CXCR4 and CXCL12-mediated chemotaxis with IC50 values of 44 nM and 5.7 nM, respectively [1].Using the CCRF CEM T-cell line that constitutively expresses CXCR4 ,Plerixafor (AMD3100) was an antagonist of SDF-1/CXCL12 ligand binding. Plerixafor (AMD3100) inhibits SDF-1 mediated GTP-binding, SDF-1 mediated calcium flux, and SDF-1 stimulated chemotaxis [1].
In U2OS cells, When Plerixafor (AMD3100) concentration was 300nM, Inhibition of cell invasion with AMD3100 was 75%[2].The cell proliferation of U87MG cells exposed to peptide R or Plerixafor (AMD3100) was evaluated.Cells treated with Plerixafor (AMD3100) showed a modest reduction in cell proliferation compared with cells stimulated with CXCL12[6].
An increased number of colony-forming MSC in the peripheral blood after injection of all compounds in a tibia fracture mouse model. However, the number and size of the colonies were highest in IGF1 plus Plerixafor (AMD3100) injected mice compared to PDGF, SCF and VEGF treated groups, in combination with Plerixafor (AMD3100).Treatment with IGF1 and Plerixafor (AMD3100) results in augmented bone growth in a mouse segmental defect model[3]. Plerixafor (AMD3100) (2 mg/kg) administration to UUO mice exacerbates renal interstitial T cell infiltration, resulting in increased production of the pro-inflammatory cytokines IL-6 and IFN-γ and decreased expression of the anti-inflammatory cytokine IL-10[4]. Both perivascular and interstitial fibrosis are significantly reduced by the CXCR4 antagonist, Plerixafor (AMD3100) at 8 weeks[5].Three adults with WHIM syndrome who received Plerixafor (Plerixafor (AMD3100)) 0.01 to 0.02 mg/kg subcutaneously twice daily for 6 months had increasing circulating white blood cells and fewer associated infections[7].
参考文献:
[1]: Zabel BA, Wang Y,et,al. Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol. 2009 Sep 1;183(5):3204-11. doi: 10.4049/jimmunol.0900269. Epub 2009 Jul 29. PMID: 19641136.
[2]: Li J, OupickY D. Effect of biodegradability on CXCR4 antagonism, transfection efficacy and antimetastatic activity of polymeric Plerixafor. Biomaterials. 2014 Jul;35(21):5572-9. doi: 10.1016/j.biomaterials.2014.03.047. Epub 2014 Apr 13. PMID: 24726746; PMCID: PMC4038967.
[3]: Kumar S, Ponnazhagan S. Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect. Bone. 2012 Apr;50(4):1012-8. doi: 10.1016/j.bone.2012.01.027. Epub 2012 Feb 9. PMID: 22342795; PMCID: PMC3339043.
[4]: Yang J, Zhu F, et,al. Continuous AMD3100 Treatment Worsens Renal Fibrosis through Regulation of Bone Marrow Derived Pro-Angiogenic Cells Homing and T-Cell-Related Inflammation. PLoS One. 2016 Feb 22;11(2):e0149926. doi: 10.1371/journal.pone.0149926. PMID: 26900858; PMCID: PMC4763993.
[5]: Chu PY, Walder K, et,al. CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis. PLoS One. 2015 Jul 27;10(7):e0133616. doi: 10.1371/journal.pone.0133616. PMID: 26214690; PMCID: PMC4516278.
[6]: Mercurio L, Ajmone-Cat MA, et,al. Targeting CXCR4 by a selective peptide antagonist modulates tumor microenvironment and microglia reactivity in a human glioblastoma model. J Exp Clin Cancer Res. 2016 Mar 25;35:55. doi: 10.1186/s13046-016-0326-y. PMID: 27015814; PMCID: PMC4807593.
[7]: McDermott DH, Liu Q, et,al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014 Apr 10;123(15):2308-16. doi: 10.1182/blood-2013-09-527226. Epub 2014 Feb 12. PMID: 24523241; PMCID: PMC3983611.
Plerixafor(AMD3100) 是 CXCR4 和 CXCL12 介导的趋化作用的小分子抑制剂，IC50 值分别为 44 nM 和 5.7 nM [1]。使用 CCRF CEM T 细胞系Plerixafor (AMD3100) 组成型表达 CXCR4，是 SDF-1/CXCL12 配体结合的拮抗剂。 Plerixafor (AMD3100) 抑制 SDF-1 介导的 GTP 结合、SDF-1 介导的钙流和 SDF-1 刺激的趋化性 [1]。
在 U2OS 细胞中，当 Plerixafor (AMD3100) 浓度为 300nM，AMD3100 对细胞侵袭的抑制率为 75%[2]。评估暴露于肽 R 或 Plerixafor (AMD3100) 的 U87MG 细胞的细胞增殖。与用 CXCL12[6] 刺激的细胞相比，AMD3100) 显示细胞增殖适度减少。
注射所有化合物后外周血中形成集落的 MSC 数量增加在胫骨骨折小鼠模型中。然而，与 PDGF、SCF 和 VEGF 联合普乐沙福 (AMD3100) 治疗组相比，IGF1 加普乐沙福 (AMD3100) 注射小鼠的菌落数量和大小最高。用 IGF1 和普乐沙福 (AMD3100) 治疗会导致骨量增加小鼠节段性缺陷模型的生长[3]。 Plerixafor (AMD3100) (2 mg/kg) 给予 UUO 小鼠会加剧肾间质 T 细胞浸润，导致促炎细胞因子 IL-6 和 IFN-γ 的产生增加；和抗炎细胞因子 IL-10[4] 的表达降低。 CXCR4 拮抗剂 Plerixafor (AMD3100) 在 8 周时显着减少了血管周围和间质纤维化[5]。三名患有 WHIM 综合征的成人接受了 Plerixafor（Plerixafor (AMD3100)）0.01 至 0.02 mg/ kg 每天两次皮下注射 6 个月，循环白细胞增加，相关感染减少[7]。
| Kinase experiment [1]: | |
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Preparation Method |
For competitive binding studies of CXCR4, different concentrations of Plerixafor (AMD3100) were incubated with CCRF-CEM cells and 100 pM 125I-SDF-1α in binding buffer for 3 h at 4 C.Competitive binding assays to remove unbound 125I-SDF-1αBLT1 using cold HEPES and NaCl washing were performed on CHO-S cell membranes. |
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Reaction Conditions |
10-12M-10-4M Plerixafor (AMD3100) with cells for 3 hours at 4 °C |
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Applications |
Plerixafor (AMD3100) is a specific antagonist of CXCR4, is not cross-reactive with other chemokine receptors, and is not an agonist of CXCR4. |
| Cell experiment [2]: | |
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Cell lines |
CXCR4+ U2OS cells |
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Preparation Method |
Tumour Invasion Assay:CXCR4+ U2OS cells were trypsinized and resuspended with different concentrations of Plerixafor (AMD3100), PAMD, or rPAMD in serum-free medium for 30 min. |
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Reaction Conditions |
0.3uM Plerixafor (AMD3100); 30 minutes |
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Applications |
When Plerixafor (AMD3100) concentration was 0.3uM, Inhibition of cell invasion with AMD3100 was 75%. |
| Animal experiment [3]: | |
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Animal models |
C57BL/6 mice with segmental bone defects |
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Preparation Method |
Mice were injected with PBS, IGF1, SCF, PDGF or VEGF for five consecutive days and on the 5th day, Plerixafor (AMD3100) (5 mg/kg i.p.) was injected in a volume of 100 μl in PBS. |
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Dosage form |
5 mg/kg Plerixafor (AMD3100); Intraperitoneal injection |
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Applications |
An increased number of colony-forming MSC in the peripheral blood after injection of all compounds in a tibia fracture mouse model . However, the number and size of the colonies were highest in IGF1 plus Plerixafor (AMD3100) injected mice compared to PDGF, SCF and VEGF treated groups, in combination with Plerixafor (AMD3100). |
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参考文献: [1]. Fricker SP, Anastassov V, et,al. Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Biochem Pharmacol. 2006 Aug 28;72(5):588-96. doi: 10.1016/j.bcp.2006.05.010. Epub 2006 Jul 3. PMID: 16815309. [2]. Li J, Oupick? D. Effect of biodegradability on CXCR4 antagonism, transfection efficacy and antimetastatic activity of polymeric Plerixafor. Biomaterials. 2014 Jul;35(21):5572-9. doi: 10.1016/j.biomaterials.2014.03.047. Epub 2014 Apr 13. PMID: 24726746; PMCID: PMC4038967. [3]. Kumar S, Ponnazhagan S. Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect. Bone. 2012 Apr;50(4):1012-8. doi: 10.1016/j.bone.2012.01.027. Epub 2012 Feb 9. PMID: 22342795; PMCID: PMC3339043. |
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