AMG 487 is an oral, selective chemokine receptor 3 (CXCR3) antagonist that inhibits CXCL10 and CXCL11 binding to CXCR3 with IC50 values of 8.0 and 8.2 nM, respectively[1].
AMG 487(1 μM AMG 487;18 h (C26 cells) or 40 h (HT29 cells)), the CXCR3 antagonist, significantly inhibited the migratory responses of the cells to each of the three ligands(rCXCL9, rCXCL10 and rCXCL11)[2].
the AMG 487-treated mice(SCID mice:1 μM AMG 487;s.c.7-17day. Balb/c mice:5 mg/kg: s.c.˙twice daily.) exhibited fewer pulmonary nodules than the control mice in both the models: a 62% reduction in the human mode and 42% less nodules in the mouse model. The inhibitory effect of AMG 487 treatment was also detectable in the cumulative tumour volume with a reduction by 58% in the lungs of the HT29-injected immunodeficient mice and by 51% in the lungs of the C26-injected syngeneic mice[2]. During in vitro differentiation, the addition of AMG 487(3- 60μM) decreased the expression of DC co-stimulatory markers, indicating that DC was in a semi-mature state[4]. 66.1 tumor cells were pretreated with AMG 487 prior to i.v. injection into immune-competent female mice. Antagonism of CXCR3 on 66.1 tumor cells inhibited experimental lung metastasis, and this antimetastatic activity was compromised in mice depleted of natural killer cells. Systemic administration of AMG 487(5 mg/kg;s.c.;twice daily) also inhibited experimental lung metastasis[3]. In mice, injection of AMG-487 (i.c.v.)significantly attenuated the accumulation of c-fos in neurons induced by polyinosinic-polycytidylic acid (PIC)[5]. WT mice treated with AMG-487 (5 μg/g twice a day) showed a 45% reduction in bone loss and decreased osteoclasts after LPS injections[6]. Meanwhile, AMG 487 treatment significantly reduced bone loss in mice[7].
参考文献:
[1]. Johnson M, Li AR,et,al. Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3339-43. doi: 10.1016/j.bmcl.2007.03.106. Epub 2007 Apr 6. PMID: 17448658.
[2]. Cambien B, Karimdjee BF, et,al. Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism. Br J Cancer. 2009 Jun 2;100(11):1755-64. doi: 10.1038/sj.bjc.6605078. Epub 2009 May 12. PMID: 19436305; PMCID: PMC2695685.
[3]. Walser TC, Rifat S, et,al. Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res. 2006 Aug 1;66(15):7701-7. doi: 10.1158/0008-5472.CAN-06-0709. PMID: 16885372.
[4]. Qin C, Liu H, et,al.In Vitro Immunological Effects of CXCR3 Inhibitor AMG487 on Dendritic Cells. Arch Immunol Ther Exp (Warsz). 2020 Apr 1;68(2):11. doi: 10.1007/s00005-020-00577-3. PMID: 32239302.
[5]. Petrisko TJ, Konat GW. Peripheral viral challenge increases c-fos level in cerebral neurons. Metab Brain Dis. 2021 Oct;36(7):1995-2002. doi: 10.1007/s11011-021-00819-z. Epub 2021 Aug 18. PMID: 34406561.
[6]. Hiyari S, Green E, et,al. Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis. J Bone Miner Res. 2018 Aug;33(8):1450-1463. doi: 10.1002/jbmr.3440. Epub 2018 May 22. PMID: 29637625; PMCID: PMC8434897.
[7]. Lari S, Hiyari S, et,al. Local delivery of a CXCR3 antagonist decreases the progression of bone resorption induced by LPS injection in a murine model. Clin Oral Investig. 2022 Aug;26(8):5163-5169. doi: 10.1007/s00784-022-04484-z. Epub 2022 Apr 25. PMID: 35462591; PMCID: PMC9710470.
AMG 487 是一种口服的选择性趋化因子受体 3 (CXCR3) 拮抗剂，可抑制 CXCL10 和 CXCL11 与 CXCR3 的结合，IC50 值分别为 8.0 和 8.2 nM[1]。
AMG 487(1 77777#181;M AMG 487;18 小时（C26 细胞）或 40 小时（HT29 细胞）），CXCR3 拮抗剂，显着抑制细胞对三种配体（rCXCL9、rCXCL10）中每一种的迁移反应和 rCXCL11)[2]。
AMG 487 处理的小鼠（SCID 小鼠:1 µ；M AMG 487；s.c.7-17day。Balb/c 小鼠:5 mg /kg:每天两次。）在两种模型中都比对照小鼠表现出更少的肺部结节:人类模式减少了 62%，小鼠模型中的结节减少了 42%。 AMG 487 治疗的抑制作用也可在累积肿瘤体积中检测到，注射 HT29 的免疫缺陷小鼠的肺部减少了 58%，注射了 C26 的同基因小鼠的肺部减少了 51%[2 ]。在体外分化过程中，AMG 487(3-60μM)的加入降低了DC共刺激标志物的表达，表明DC处于半成熟状态[4]。 66.1 个肿瘤细胞在静脉注射前用 AMG 487 预处理。注射到具有免疫能力的雌性小鼠体内。 CXCR3 对 66.1 肿瘤细胞的拮抗作用抑制了实验性肺转移，并且这种抗转移活性在自然杀伤细胞耗尽的小鼠中受到损害。 AMG 487（5 mg/kg；s.c.；每日两次）的全身给药也抑制了实验性肺转移[3]。在小鼠中，注射 AMG-487 (i.c.v.) 可显着减弱聚肌胞苷酸 (PIC) 诱导的神经元中 c-fos 的积累[5]。用 AMG-487（5 77777#181；g/g，每天两次）处理的 WT 小鼠在注射 LPS 后骨质流失减少了 45%，破骨细胞也减少了[6]。同时，AMG 487 治疗显着减少了小鼠的骨质流失[7]。
| Cell experiment [1]: | |
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Cell lines |
C26 cells and HT29 cells |
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Preparation Method |
Cells treated or not with 1 μM AMG487 or dimethyl sulfoxide (DMSO) vehicle were placed in the upper well and various concentrations of human or mouse rCXCL9, rCXCL10 and rCXCL11 were added to the lower wells. After incubation of the plates for 18 h (C26 cells) or for 40 h (HT29 cells) at 37 C in 5% CO2 atmosphere, non-migrated cells were removed from the upper well and the migrated cells collected on the lower side of the insert were stained using crystal violet dye and enumerated. |
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Reaction Conditions |
1 μM AMG487;18 h (C26 cells) or 40 h (HT29 cells) |
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Applications |
AMG 487, the CXCR3 antagonist, significantly inhibited the migratory responses of the cells to each of the three ligands(rCXCL9, rCXCL10 and rCXCL11). |
| Animal experiment [2]: | |
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Animal models |
SCID and Balb/c mice |
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Preparation Method |
For the induction of pulmonary metastases, HT29 cells or C26 cells were delivered by intravenous tail injection into SCID or Balb/c mice, respectively. For the polymetastatic liver model, HT29 cells or C26 cells were injected intravenously into the portal vein of Nude or Balb/c mice, respectively. The curative treatment of the mice-bearing metastases was achieved by treating the animals twice daily on days +5 to +12 (syngeneic C26 model) or on days +5 to +23 (immunodeficient HT29 model) with subcutaneous injections of 5 mg/kg of AMG 487 or vehicle. The preventive treatment to antagonise CXCR3 was performed by incubating the colon cancer cells with 1 μM of AMG 487 or vehicle for 18 h in vitro before their injection into mice and by treating concomitantly the animals twice daily on days 1 and 0 with subcutaneous injections of 5 mg/kg of AMG487 or vehicle. |
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Dosage form |
SCID :1 μM AMG 487;s.c.7-17day. |
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Applications |
The AMG 487-treated mice exhibited fewer pulmonary nodules than the control mice in both the models: a 62% reduction in the human mode and 42% less nodules in the mouse model. The inhibitory effect of AMG 487 treatment was also detectable in the cumulative tumour volume with a reduction by 58% in the lungs of the HT29-injected immunodeficient mice and by 51% in the lungs of the C26-injected syngeneic mice. |
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参考文献: [1]. Cambien B, Karimdjee BF, et,al.Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism. Br J Cancer. 2009 Jun 2;100(11):1755-64. doi: 10.1038/sj.bjc.6605078. Epub 2009 May 12. PMID: 19436305; PMCID: PMC2695685. |
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