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, Beilei1,2,3; Wu, Jiaxin1,2,3; Wu, Yun1,3; Chen, Cheng1,2,3; Zou, Fengming1,3; Wang, Aoli1,3; Wu, Hong1,3; Hu, Zhenquan1,3; Jiang, Zongru1,2,3; Liu, Qingwang1,4 | |
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. |
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