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]。