Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors

doi:10.1016/j.ejmech.2022.114782

	Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors
	Liang, Xiaofei 1,5; Wang, Chun 2,5; Wang, Beilei 1; Liu, Juan 1,5; Qi, Shuang 1,5; Wang, Aoli 1,5; Liu, Qingwang 1,5; Deng, Maoqing 2,5; Wang, Li 1,5; Liu, Jing 1,2,4,5
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2022-12-05
卷号	243
关键词	CSF1R inhibitor Kinase inhibitor Macrophage polarization
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2022.114782
通讯作者	Liu, Jing(jingliu@hmfl.ac.cn) ; Liu, Qingsong(qsliu97@hmfl.ac.cn)
英文摘要	Colony stimulating factor 1 receptor kinase (CSF1R) plays an integral role in tumor-associated macrophage repolarization and has emerged as a novel therapeutic target for cancer immunotherapy. Most of the current CSF1R kinase inhibitors lack selectivity between CSF1R kinase and other type III growth factor receptor mem-bers. Herein, we report a potent and selective CSF1R inhibitor 18h, which displays an IC50 value of 5.14 nM against CSF1R and achieves selectivity over other type III receptor tyrosine kinases (>38-fold). 18h inhibits the phosphorylation of CSF1R and its downstream signaling pathway in RAW264.7, THP-1, and M-NFS-60 cells. Treatment with this compound leads to alteration of the macrophage polarization in RAW264.7 macrophages in a dose-dependent manner. In vivo, 18h demonstrates acceptable pharmacokinetic profiles and suppresses the tumor growth in a mouse xenograft model inoculated with M-NFS-60 cells.
资助项目	National Natural Science Foundation of China[82173671] ; National Natural Science Foundation of China[81872745] ; National Natural Science Foundation of China[82103976] ; Natural Science Foundation of Anhui Province[2108085J42] ; Natural Science Foundation of Anhui Province[2108085QH377] ; Plan for Major Anhui Provincial Science and Technology Project[202003a07020006] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; CASHIPS Director's Fund[YZJJ2021QN38] ; Youth Innovation Promotion Association of CAS[Y202088]
WOS关键词	MACROPHAGES ; CANCER ; POLARIZATION ; ANTITUMOR ; CELLS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000870590900003
资助机构	National Natural Science Foundation of China ; Natural Science Foundation of Anhui Province ; Plan for Major Anhui Provincial Science and Technology Project ; Frontier Science Key Research Program of CAS ; CASHIPS Director's Fund ; Youth Innovation Promotion Association of CAS
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/129827]
专题	中国科学院合肥物质科学研究院
通讯作者	Liu, Jing; Liu, Qingsong
作者单位	1.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Anhui, Peoples R China 2.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China 3.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China 4.Chinese Acad Sci, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China 5.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Hlth & Med Technol, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Liang, Xiaofei,Wang, Chun,Wang, Beilei,et al. Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,243.
APA	Liang, Xiaofei.,Wang, Chun.,Wang, Beilei.,Liu, Juan.,Qi, Shuang.,...&Liu, Qingsong.(2022).Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,243.
MLA	Liang, Xiaofei,et al."Discovery of Pyrrolo[2,3-d]pyrimidine derivatives as potent and selective colony stimulating factor 1 receptor kinase inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 243(2022).