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Chinese Academy of Sciences Institutional Repositories Grid
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  2. 合肥物质科学研究院
  3. 中国科学院合肥物质科学研究院
  4. 中科院强磁场科学中心
Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3K delta) inhibitor

文献类型：期刊论文

作者Liang, Xiaofei4,6; Li, Feng5,6; Chen, Cheng5,6; Jiang, Zongru5,6; Wang, Aoli4,6; Liu, Xiaochuan4,6; Ge, Juan3; Hu, Zhenquan4,6; Yu, Kailin4,6; Wang, Wenliang5,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2018-08-05
卷号156页码:831-846
ISSN号0223-5234
关键词PI3K delta Kinase inhibitor Acute myeloid leukemia Structure-activity relationship
DOI10.1016/j.ejmech.2018.07.036
通讯作者Liu, Qingsong(qsliu97@hmfl.ac.cn) ; Liu, Jing(jingliu@hmfl.ac.cn)
英文摘要PI3K delta, which is mainly expressed in leukocytes, plays a critical role in B-cell receptor mediated signaling pathway and has been extensively studied as a drug discovery target for B cell malignances such as AML, CLL etc. In this manuscript, we report the discovery, SAR optimization and pharmacological evaluation of a novel series of aminothiazole-pyridine containing PI3K delta inhibitors. Among them compound 151 (CHMFL-PI3K delta-317) displays an IC50 of 6 nM against PI3K delta in the ADP-Glo biochemical assays. It also exhibits over 10-1500 fold selectivity over other class I, II and III PIKK family isoforms. In addition, in the cellular context, 15i can selectively and potently inhibit PI3K delta mediated phosphorylation of Akt T308 but not PI3K delta, beta, gamma mediated Akt phosphorylation. 15i also exhibits an excellent selectivity profile in the protein kinases including 468 kinases/mutants at the concentration of 1 mu M. 15i has acceptable pharmacokinetic properties and can dose-dependently inhibit the tumor growth of AML cell line MOLM14 inoculated xenograft mouse model. The high selectivity and potency makes 15i a potential valuable addition to the current PI3K delta armory. (C) 2018 Elsevier Masson SAS. All rights reserved.
WOS关键词SMALL-MOLECULE INHIBITORS ; PI3 KINASE ; MALIGNANCIES ; CANCER ; DISEASE ; GAMMA ; BETA
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[81402797] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020350] ; Science and Technology Projects of Anhui Province[16030801114] ; Science and Technology Projects of Anhui Province[1704a0802140] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; National Program for Support of Top Notch Young Professionals ; Youth Innovation Promotion Association of CAS[2016385] ; CAS/SAFEA International Partnership Program for Creative Research Teams
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:000443663200061
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 Natural Science Foundation of China ; 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 Natural Science Foundation of China ; 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 Natural Science Foundation of China ; 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 Natural Science Foundation of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; 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源URL[http://ir.hfcas.ac.cn:8080/handle/334002/38555]  
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, Qingsong; Liu, Jing
作者单位1.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Anhui, Peoples R China
2.Precis Med Res Lab Anhui Prov, Hefei 230088, Anhui, Peoples R China
3.Chinese Acad Sci, Hefei Inst Phys Sci, Inst Technol Innovat, Precis Targeted Therapy Discovery Ctr, Hefei 230088, Anhui, Peoples R China
4.CHMFL HCMTC Target Therapy Joint Lab, 350 Shushanhu Rd, Hefei 230031, Anhui, Peoples R China
5.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
6.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China
7.Hefei Cosource Med Technol Co LTD, 358 Ganquan Rd, Hefei 230031, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xiaofei,Li, Feng,Chen, Cheng,et al. Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3K delta) inhibitor[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,156:831-846.
APA Liang, Xiaofei.,Li, Feng.,Chen, Cheng.,Jiang, Zongru.,Wang, Aoli.,...&Liu, Jing.(2018).Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3K delta) inhibitor.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,156,831-846.
MLA Liang, Xiaofei,et al."Discovery of (S)-2-amino-N-(5-(6-chloro-5-(3-methylphenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)-3-methylbutanamide (CHMFL-PI3KD-317) as a potent and selective phosphoinositide 3-kinase delta (PI3K delta) inhibitor".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 156(2018):831-846.

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