Plerixafor (AMD3100)
(Synonyms: 普乐沙福; AMD 3100; JM3100; SID791) 目录号 : GC14745
An antagonist of CXCR4
Cas No.:110078-46-1
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Kinase experiment [1]: | |
|
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. |
|
Reaction Conditions |
10-12M-10-4M Plerixafor (AMD3100) with cells for 3 hours at 4 °C |
|
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]: | |
|
Cell lines |
CXCR4+ U2OS cells |
|
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. |
|
Reaction Conditions |
0.3uM Plerixafor (AMD3100); 30 minutes |
|
Applications |
When Plerixafor (AMD3100) concentration was 0.3uM, Inhibition of cell invasion with AMD3100 was 75%. |
| Animal experiment [3]: | |
|
Animal models |
C57BL/6 mice with segmental bone defects |
|
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. |
|
Dosage form |
5 mg/kg Plerixafor (AMD3100); Intraperitoneal injection |
|
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). |
|
References: [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. |
|
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].
References:
[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, OupickÝ 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]。
| Cas No. | 110078-46-1 | SDF | |
| 别名 | 普乐沙福; AMD 3100; JM3100; SID791 | ||
| 化学名 | 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane | ||
| Canonical SMILES | C1CNCCNCCCN(CCNC1)CC2=CC=C(C=C2)CN3CCCNCCNCCCNCC3 | ||
| 分子式 | C28H54N8 | 分子量 | 502.78 |
| 溶解度 | ≥ 25.1mg/mL in Ethanol, ≥ 2.9mg/mL in Water with gentle warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.9889 mL | 9.9447 mL | 19.8894 mL |
| 5 mM | 0.3978 mL | 1.9889 mL | 3.9779 mL |
| 10 mM | 0.1989 mL | 0.9945 mL | 1.9889 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
CXCR4 antagonist AMD3100 (plerixafor): From an impurity to a therapeutic agent
Pharmacol Res2020 Sep;159:105010.PMID: 32544428DOI: 10.1016/j.phrs.2020.105010
AMD3100 (plerixafor), a CXCR4 antagonist, has opened a variety of avenues for potential therapeutic approaches in different refractory diseases. The CXCL12/CXCR4 axis and its signaling pathways are involved in diverse disorders including HIV-1 infection, tumor development, non-Hodgkin lymphoma, multiple myeloma, WHIM Syndrome, and so on. The mechanisms of action of AMD3100 may relate to mobilizing hematopoietic stem cells, blocking infection of X4 HIV-1, increasing circulating neutrophils, lymphocytes and monocytes, reducing myeloid-derived suppressor cells, and enhancing cytotoxic T-cell infiltration in tumors. Here, we first revisit the pharmacological discovery of AMD3100. We then review monotherapy of AMD3100 and combination use of AMD3100 with other agents in various diseases. Among those, we highlight the perspective of AMD3100 as an immunomodulator to regulate immune responses particularly in the tumor microenvironment and synergize with other therapeutics. All the pre-clinical studies support the clinical testing of the monotherapy and combination therapies with AMD3100 and further development for use in humans.
Mozobil? (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration
Antivir Chem Chemother2019 Jan-Dec;27:2040206619829382.PMID: 30776910DOI: 10.1177/2040206619829382
AMD3100 (plerixafor, Mozobil?) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34+stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin's Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome.
AMD3100/Plerixafor overcomes immune inhibition by the CXCL12-KRT19 coating on pancreatic and colorectal cancer cells
Br J Cancer2021 Jul;125(2):149-151.PMID: 33772153DOI: 10.1038/s41416-021-01315-y
A recent Phase 1 clinical study of the immunological effects of inhibiting the chemokine receptor, CXCR4, in patients with pancreatic ductal adenocarcinoma or colorectal cancer suggests that stimulation of CXCR4 on immune cells suppresses the intratumoural immune reaction. Here, we discuss how CXCR4 mediates this response, and how cancer cells elicit it.
Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment
FASEB J2019 May;33(5):6596-6608.PMID: 30802149DOI: 10.1096/fj.201802067RR
Blockade of immune-checkpoint programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 can enhance effector T-cell responses. However, the lack of response in many patients to checkpoint-inhibitor therapies emphasizes the need for combination immunotherapies to pursue maximal antitumor efficacy. We have previously demonstrated that antagonism of C-X-C chemokine receptor type 4 (CXCR4) by plerixafor (AMD3100) can decrease regulatory T (Treg)-cell intratumoral infiltration. Therefore, a combination of these 2 therapies might increase antitumor effects. Here, we evaluated the antitumor efficacy of AMD3100 and anti-PD-1 (¦ÁPD-1) antibody alone or in combination in an immunocompetent syngeneic mouse model of ovarian cancer. We found that AMD3100, a highly specific CXCR4 antagonist, directly down-regulated the expression of both C-X-C motif chemokine 12 (CXCL12) and CXCR4 in vitro and in vivo in tumor cells. AMD3100 and ¦ÁPD-1 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice when given as monotherapy. Combination of these 2 agents significantly enhanced antitumor effects compared with single-agent administration. Benefits of tumor control and animal survival were associated with immunomodulation mediated by these 2 agents, which were characterized by increased effector T-cell infiltration, increased effector T-cell function, and increased memory T cells in tumor microenvironment. Intratumoral Treg cells were decreased, and conversion of Treg cells into T helper cells was increased by AMD3100 treatment. Intratumoral myeloid-derived suppressor cells were decreased by the combined treatment, which was associated with decreased IL-10 and IL-6 in the ascites. Also, the combination therapy decreased suppressive leukocytes and facilitated M2-to-M1 macrophage polarization in the tumor. These results suggest that AMD3100 could be used to target the CXCR4-CXCL12 axis to inhibit tumor growth and prevent multifaceted immunosuppression alone or in combination with ¦ÁPD-1 in ovarian cancer, which could be clinically relevant to patients with this disease.-Zeng, Y., Li, B., Liang, Y., Reeves, P. M., Qu, X., Ran, C., Liu, Q., Callahan, M. V., Sluder, A. E., Gelfand, J. A., Chen, H., Poznansky, M. C. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.
Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil?) and potential of other CXCR4 antagonists as stem cell mobilizers
Pharmacol Ther2010 Dec;128(3):509-18.PMID: 20826182DOI: 10.1016/j.pharmthera.2010.08.009
AMD3100 was originally discovered as an anti-HIV agent effective in inhibiting the replication of HIV in vitro at nanomolar concentrations. We found it to be a potent and selective antagonist of CXCR4, the receptor for the chemokine SDF-1 (now called CXCL12). AMD3100 was then developed, and marketed, as a stem cell mobilizer, and renamed plerixafor (Mozobil?). The path to the discovery of Mozobil? as a stem cell mobilizer was described in Biochem. Pharmacol. 77: 1655-1664 (2009). Here I review the recent advances that have consolidated the role of plerixafor in mobilizing hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) from the bone marrow into the blood circulation. Plerixafor acts synergistically with granulocyte colony-stimulating factor (G-CSF), and its usefulness has been proven particularly for the mobilization of HSCs and HPCs for autologous stem cell transplantation in patients with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM). Plerixafor also has great potential for the treatment of hematological malignancies other than NHL and MM, and non-hematological malignancies, and, eventually, several other diseases depending on the CXCL12-CXCR4 interaction. Various AMD3100 analogs have been described (i.e. AMD11070, AMD3465, KRH-3955, T-140, and 4F-benzoyl-TN14003), primarily as potential anti-HIV agents. They are all strong CXCR4 antagonists. Their role in stem cell mobilization remains to be assessed.