Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds

doi:10.1038/s41401-018-0087-6

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	Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds
	Gong, Grace Qun 3; Wang, Ke 4; Dai, Xin-Chuan 3; Zhou, Yan 3; Basnet, Rajesh 3; Chen, Yi3 ; Yang, De-Hua3 ; Lee, Woo-Jeong 1; Buchanan, Christina Maree 1; Flanagan, Jack Urquhart 2
刊名	Acta pharmacologica Sinica
	2018-12
卷号	39 期号:12 页码:1902-1912
ISSN号	1745-7254
DOI	10.1038/s41401-018-0087-6
文献子类	Article
英文摘要	The serum and glucocorticoid-regulated kinase (SGK) family has been implicated in the regulation of many cellular processes downstream of the PI3K pathway. It plays a crucial role in PI3K-mediated tumorigenesis, making it a potential therapeutic target for cancer. SGK family consists of three isoforms (SGK1, SGK2, and SGK3), which have high sequence homology in the kinase domain and similar substrate specificity with the AKT family. In order to identify novel compounds capable of inhibiting SGK3 activity, a high-throughput screening campaign against 50,400 small molecules was conducted using a fluorescence-based kinase assay that has a Z' factor above 0.5. It identified 15 hits (including nitrogen-containing aromatic, flavone, hydrazone, and naphthalene derivatives) with IC values in the low micromolar to sub-micromolar range. Four compounds with a similar scaffold (i.e., a hydrazone core) were selected for structural modification and 18 derivatives were synthesized. Molecular modeling was then used to investigate the structure-activity relationship (SAR) and potential protein-ligand interactions. As a result, a series of SGK inhibitors that are active against both SGK1 and SGK3 were developed and important functional groups that control their inhibitory activity identified.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266321]
专题	国家新药筛选中心
通讯作者	Chen, Ying; Wang, Ming-Wei
作者单位	1.Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand; 2.The Maurice Wilkins Centre, Auckland, New Zealand 3.The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China; 4.School of Pharmacy, Fudan University, Shanghai, 201203, China;
推荐引用方式 GB/T 7714	Gong, Grace Qun,Wang, Ke,Dai, Xin-Chuan,et al. Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds[J]. Acta pharmacologica Sinica,2018,39(12):1902-1912.
APA	Gong, Grace Qun.,Wang, Ke.,Dai, Xin-Chuan.,Zhou, Yan.,Basnet, Rajesh.,...&Wang, Ming-Wei.(2018).Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds.Acta pharmacologica Sinica,39(12),1902-1912.
MLA	Gong, Grace Qun,et al."Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds".Acta pharmacologica Sinica 39.12(2018):1902-1912.