Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R
Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R
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DOI：
10.1038/s41401-018-0056-0
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发表时间：
2018-11-01
影响因子：
8.2
通讯作者：
Ding, Jian
中科院分区：
文献类型：
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作者：
Liu, Ying-Qiang;Wang, Ya-Nan;Ding, Jian
集落刺激因子1受体（CSF 1 R）在促进各种类型肿瘤的进展中起着关键作用。在这里，我们确定D2923作为一种新的和选择性的抑制剂的CSF 1 R，并探讨其在体外和体内的抗肿瘤活性。D2923有效抑制CSF 1 R体外激酶活性，IC 50值为0.3 nM。它对一组测试的激酶的效力低10至300倍。D2923可明显阻断CSF-1诱导的THP-1和RAW264.7巨噬细胞CSF 1 R活化及其下游信号转导，从而抑制巨噬细胞的体外生长。此外，D2923剂量依赖性地减弱了一小组髓性白血病细胞的增殖，主要是通过将细胞阻滞在G1期以及诱导细胞凋亡。体内实验结果进一步证明，D2923对M-NFS-60异种移植物显示出有效的抗肿瘤活性，在40和80 mg/kg剂量下肿瘤生长抑制率分别为50%和88%。此外，D2923耐受性良好，与对照组相比，在给药组中未观察到显著体重减轻。Western blot分析和免疫组化结果证实，D2923处理后肿瘤组织中CSF 1 R的磷酸化显著降低，并且这伴随着肿瘤中巨噬细胞的消耗。同时，与对照组相比，D2923处理组中增殖标志物Ki 67的表达也显著降低。综上所述，我们确定D2923是一种新的和有效的CSF 1 R抑制剂，值得进一步研究。
Colony-stimulating factor 1 receptor (CSF1R) plays a critical role in promoting tumor progression in various types of tumors. Here, we identified D2923 as a novel and selective inhibitor of CSF1R and explored its antitumor activity both in vitro and in vivo. D2923 potently inhibited CSF1R in vitro kinase activity with an IC50 value of 0.3 nM. It exhibited 10- to 300-fold less potency against a panel of kinases tested. D2923 markedly blocked CSF-1-induced activation of CSF1R and its downstream signaling transduction in THP-1 and RAW264.7 macrophages and thus inhibited the in vitro growth of macrophages. Moreover, D2923 dose-dependently attenuated the proliferation of a small panel of myeloid leukemia cells, mainly by arresting the cells at G1 phase as well as inducing apoptosis in the cells. The results of the in vivo experiments further demonstrated that D2923 displayed potent antitumor activity against M-NFS-60 xenografts, with tumor growth inhibition rates of 50% and 88% at doses of 40 and 80 mg/kg, respectively. Additionally, D2923 was well tolerated with no significant body-weight loss observed in the treatment groups compared with the control. Furthermore, a western blot analysis and the immunohistochemistry results confirmed that the phosphorylation of CSF1R in tumor tissue was dramatically reduced after D2923 treatment, and this was accompanied by the depletion of macrophages in the tumor. Meanwhile, the expression of the proliferation marker Ki67 was also markedly decreased in the D2923 treatment group compared with the control group. Taken together, we identified D2923 as a novel and effective CSF1R inhibitor, which deserves further investigation.