GW2580
目录号 : GC17286
GW2580是一种集落刺激因子-1受体（CSF-1R）的选择性和口服生物利用性抑制剂，IC50为30nM，在0.06μM时完全抑制人类c-Fms激酶。
Cas No.:870483-87-7
Sample solution is provided at 25 µL, 10mM.
GW2580 is a selective and orally bioavailable inhibitor of colony-stimulating factor-1 receptor (CSF-1R), with an IC50 of 30nM, and completely inhibits the human c-Fms kinase at 0.06μM [1]. CSF-1R (c-Fms) is a receptor tyrosine kinase of the platelet-derived growth factor receptor family, playing a crucial role in hematopoiesis, regulating proliferation, the cell survival and maturation of microglia and monocytes, and controlling the overall immune response [2]. GW2580 has been proven to inhibit the CSF-1R signaling in epithelial cells, reduce the expansion of myeloid cells (MDSCs), and alleviate the immunosuppressive microenvironment [3-4].
In vitro, GW2580 (10, 100, and 1000nM; 6; 24, 48, and 72h) dose-dependently inhibited the cell viability of mouse bone marrow-derived macrophages (BMDMs) stimulated by colony-stimulating factor-1 (CSF-1), with an IC50 of approximately 100nM [5]. GW2580 (0-5μM; 48h) treatment significantly inhibited the expression of Ndufs8, Prdx2, Prdx5, and Gpx4 in primary mouse microglia stimulated by CSF1, without affecting cell viability [6].
In vivo, after GW2580 treatment (60mg/kg/day for 14 days; oral gavage), the total CD45+CD11b+ myeloid cells in the tumors of mice subcutaneously implanted with 3LL tumor cells decreased by more than two-fold, and CD11b+F4/80+TAM also decreased by more than two-fold [5]. GW2580 (0.1% diet, 150mg/kg/day; 1 week) treatment could improve the motor function of spinal cord injury (SCI) mice, inhibit the proliferation of mouse microglia, regulate the neuroglial reactivity, and increase the density of intact myelin fibers in the tail lesion [7].
References:
[1] Conway JG, McDonald B, Parham J, et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci U S A. 2005;102(44):16078-16083.
[2] Hume D A, MacDonald K P A. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling[J]. Blood, The Journal of the American Society of Hematology, 2012, 119(8): 1810-1820.
[3] Fermi V, Warta R, Wöllner A, et al. Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580[J]. Clinical Cancer Research, 2023, 29(22): 4685-4697.
[4] Kuhn S, Yang J, Ronchese F. Monocyte-derived dendritic cells are essential for CD8+ T cell activation and antitumor responses after local immunotherapy[J]. Frontiers in immunology, 2015, 6: 584.
[5] Priceman SJ, Sung JL, Shaposhnik Z, et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood. 2010;115(7):1461-1471.
[6] Soto-Diaz K, Vailati-Riboni M, Louie AY, McKim DB, Gaskins HR, Johnson RW, Steelman AJ. Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species. Front Immunol. 2021 Nov 26;12:734349.
[7] Poulen G, Aloy E, Bringuier C M, et al. Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates[J]. Theranostics, 2021, 11(18): 8640.
GW2580是一种集落刺激因子-1受体（CSF-1R）的选择性和口服生物利用性抑制剂，IC50为30nM，在0.06μM时完全抑制人类c-Fms激酶 [1]。CSF-1R（c-Fms）是血小板衍生生长因子受体（PDGFR）家族的受体蛋白酪氨酸激酶，在造血、调节增殖、小胶质细胞和单核细胞的细胞存活和成熟以及控制整体免疫反应方面发挥着重要作用 [2]。GW2580已被证明能抑制上皮细胞的CSF-1R信号传导，减少髓系细胞（MDSCs）的扩增，并缓解免疫抑制性微环境 [3-4]。
在体外，GW2580（10, 100, and 1000nM; 6; 24, 48, and 72h）剂量依赖性地抑制了集落刺激因子-1（CSF-1）刺激的小鼠骨髓衍生的巨噬细胞（BMDMs）的细胞活力，IC50约为100nM [5]。GW2580（0-5μM; 48h）处理显著抑制了CSF1刺激的原代小鼠小胶质细胞中Ndufs8，Prdx2，Prdx5和Gpx4的表达，而不影响细胞活力 [6]。
在体内，GW2580（60mg/kg/day for 14 days; oral gavage）治疗后，皮下植入3LL肿瘤细胞小鼠的肿瘤中总CD45+CD11b+髓样细胞减少了2倍以上，CD11b+F4/80+TAM也显著减少了2倍以上 [5]。GW2580（0.1% diet, 150mg/kg/day; 1 weeks）治疗可改善脊髓损伤（SCI）小鼠运动功能，抑制小鼠小胶质细胞增殖，调节神经胶质反应性，并提高了尾段病变的完整髓鞘纤维密度 [7]。
| Cell experiment [1]: | |
Cell lines | BMDMs cells |
Preparation Method | Cell viability studies were performed using murine bone marrow–derived macrophages (BMDMs). Briefly, mouse bone marrow cells were harvested by flushing the tibias and femurs of adult C57BL/6 mice followed by red blood cell (RBC) lysis. Cells were cultured for 5 to 7 days in complete DMEM with 10ng/mL mouse CSF-1. BMDMs (1.5 × 104 cells/well in 96-well plates) were incubated with 10 or 50ng/mL CSF-1 in the presence or absence of GW2580. GW2580 was dissolved in dimethyl sulfoxide at 25mM and stored at −20°C. Cell viability was measured at indicated time points using the CCK-8 assay. |
Reaction Conditions | 10, 100, and 1000nM; 6; 24, 48, and 72h |
Applications | The GW2580 dose-dependently inhibited the cell viability of BMDMs stimulated by CSF-1, with an IC50 value of approximately 100nM. |
| Animal experiment [2]: | |
Animal models | C57BL/6 mice |
Preparation Method | 3LL cells (2 × 105 cells) and B16F1 cells (105 cells) were implanted subcutaneously above the right shoulder of C57BL/6 male mice. Mice were treated with control diluent (0.5% hydroxypropyl methylcellulose; 0.1% Tween20 in distilled H2O) or GW2580 by oral gavage beginning 1 day after tumor implantation. Mice were treated with 160mg/kg GW2580 daily by oral gavage. Tumor size was measured by digital calipers as previously described. Mice were killed and tissues were analyzed using flow cytometry at the ethical tumor size limit of 1cm in diameter. |
Dosage form | 60mg/kg/day for 14 days; oral gavage. |
Applications | After treatment with GW2580, the total number of CD45+CD11b+ myeloid cells in the tumors of mice with 3LL tumor cells was reduced by more than twice, and the number of CD11b+F4/80+TAM also decreased by more than twice. |
References: | |
| Cas No. | 870483-87-7 | SDF | |
| 化学名 | 5-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]pyrimidine-2,4-diamine | ||
| Canonical SMILES | COC1=CC=C(C=C1)COC2=C(C=C(C=C2)CC3=CN=C(N=C3N)N)OC | ||
| 分子式 | C20H22N4O3 | 分子量 | 366.41 |
| 溶解度 | ≥ 36.6mg/mL in DMSO 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。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7292 mL | 13.6459 mL | 27.2918 mL |
| 5 mM | 545.8 μL | 2.7292 mL | 5.4584 mL |
| 10 mM | 272.9 μL | 1.3646 mL | 2.7292 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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.
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