Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R

doi:10.1038/s41401-018-0056-0

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R
	Liu, Ying-Qiang 2,3,5; Wang, Ya-Nan 2,3,4; Lu, Xiao-Yun 1; Tong, Lin-Jiang 2; Li, Yan 2; Zhang, Tao 2,3,4; Xun, Qiu-Ju 1,3; Feng, Fang 2; Chen, Yu-Zhe 2,3; Su, Yi 2
刊名	ACTA PHARMACOLOGICA SINICA
	2018-11
卷号	39 期号:11 页码:1768-1776
关键词	CSF-1R small-molecule inhibitor macrophage myeloid leukemia
ISSN号	1671-4083
DOI	10.1038/s41401-018-0056-0
文献子类	Article
英文摘要	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.
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020203] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020209] ; Personalized Medicines, Molecular Signature-based Drug Discovery and Development[00000000]
WOS关键词	COLONY-STIMULATING FACTOR ; RECEPTOR TYROSINE KINASES ; MACROPHAGE POLARIZATION ; RHEUMATOID-ARTHRITIS ; CANCER-IMMUNOTHERAPY ; SELECTIVE INHIBITOR ; CSF-1R INHIBITOR ; PROGENITOR-CELL ; BLOCKADE ; GROWTH
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000448392900010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279518]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Li, Yan-Li; Xie, Hua; Ding, Jian
作者单位	1.Jinan Univ, Sch Pharm, 601 Huangpu Ave, West Guangzhou 510632, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China; 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 5.Shanghai Univ, Sch Life Sci, Shanghai 200444, Peoples R China;
推荐引用方式 GB/T 7714	Liu, Ying-Qiang,Wang, Ya-Nan,Lu, Xiao-Yun,et al. Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R[J]. ACTA PHARMACOLOGICA SINICA,2018,39(11):1768-1776.
APA	Liu, Ying-Qiang.,Wang, Ya-Nan.,Lu, Xiao-Yun.,Tong, Lin-Jiang.,Li, Yan.,...&Ding, Jian.(2018).Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R.ACTA PHARMACOLOGICA SINICA,39(11),1768-1776.
MLA	Liu, Ying-Qiang,et al."Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R".ACTA PHARMACOLOGICA SINICA 39.11(2018):1768-1776.