Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino) cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl) tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor

doi:10.1016/j.ejmech.2018.09.025

CORC > 合肥物质科学研究院 > 中国科学院合肥物质科学研究院 > 中科院强磁场科学中心

	Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino) cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl) tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor
	Wang, Beilei 1,2,3; Wu, Jiaxin 1,2,3; Wu, Yun 1,3; Chen, Cheng 1,2,3; Zou, Fengming 1,3; Wang, Aoli 1,3; Wu, Hong 1,3; Hu, Zhenquan 1,3; Jiang, Zongru 1,2,3; Liu, Qingwang 1,4
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-10-05
卷号	158 页码:896-916
关键词	CDK9 Kinase inhibitor Structure-activity relationship Leukemia
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.09.025
通讯作者	Liu, Jing(jingliu@hmfl.ac.cn) ; Liu, Qingsong(qsliu97@hmfl.ac.cn)
英文摘要	Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1)= 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[U1432250] ; National Natural Science Foundation of China[81471773] ; National Natural Science Foundation of China[81473088] ; National Natural Science Foundation of China[U1532154] ; National Natural Science Foundation of China[81703559] ; National Natural Science Foundation of China[81703007] ; National Natural Science Foundation of China[21708044] ; National Key Research and Development Program of China[2016YFA0400900] ; Major Science and Technology Program of Anhui Province[16030801114] ; China Postdoctoral Science Foundation[2018M630721] ; China Postdoctoral Science Foundation[2018T110633] ; China Postdoctoral Science Foundation[2018T110634] ; Natural Science Foundation of Anhui Province[1808085MH268] ; Natural Science Foundation of Anhui Province[1708085MH208] ; Natural Science Foundation of Anhui Province[1808085MH274] ; Natural Science Foundation of Anhui Province[1808085QH263] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; National Program for Support of Top-Notch Young Professionals ; Hefei leading talent in 2017
WOS关键词	CYCLIN-DEPENDENT KINASES ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; DINACICLIB SCH 727965 ; CANCER-THERAPY ; TARGETS ; 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:000448094000058
资助机构	National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; Major Science and Technology Program of Anhui Province ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; China Postdoctoral Science Foundation ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Natural Science Foundation of Anhui Province ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; Frontier Science Key Research Program of CAS ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; National Program for Support of Top-Notch Young Professionals ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017 ; Hefei leading talent in 2017
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/40061]
专题	合肥物质科学研究院_中科院强磁场科学中心
通讯作者	Liu, Jing; Liu, Qingsong
作者单位	1.Chinese Acad Sci, High Magnet Field Lab, Mailbox 1110,350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China 2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China 3.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Anhui, Peoples R China 4.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China 5.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China 6.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Anhui, Peoples R China
推荐引用方式 GB/T 7714	Wang, Beilei,Wu, Jiaxin,Wu, Yun,et al. Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino) cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl) tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,158:896-916.
APA	Wang, Beilei.,Wu, Jiaxin.,Wu, Yun.,Chen, Cheng.,Zou, Fengming.,...&Liu, Qingsong.(2018).Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino) cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl) tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,158,896-916.
MLA	Wang, Beilei,et al."Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino) cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl) tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 158(2018):896-916.