4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

doi:10.1016/j.bmc.2014.05.028

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	4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B
	Zhi, Ying 1; Gao, Li-Xin 3; Jin, Yi2 ; Tang, Chun-Lan 3; Li, Jing-Ya3 ; Li, Jia3 ; Long, Ya-Qiu 1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2014-07-15
卷号	22 期号:14 页码:3670-3683
关键词	Protein tyrosine phosphatase 1B inhibitor 4-Quinolone-3-carboxylic acid Bidentate ligand Bioisostere Insulin receptor signaling
ISSN号	0968-0896
DOI	10.1016/j.bmc.2014.05.028
文献子类	Article
英文摘要	Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies. (C) 2014 Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[81325020] ; National Natural Science Foundation of China[81361120410] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[91213303] ; National Natural Science Foundation of China[81123004] ; National Natural Science Foundation of China[21262043]
WOS关键词	INSULIN-RECEPTOR ; INTEGRASE INHIBITORS ; BINDING-SITE ; PTP1B ; OBESITY ; MICE ; RESISTANCE ; IDENTIFICATION ; SENSITIVITY ; ADIPOSITY
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000337991100010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276988]
专题	国家新药筛选中心药物化学研究室药物安全性评价中心
通讯作者	Li, Jia
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Yunnan Univ, Sch Chem Sci & Technol, Kunming 650091, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Zhi, Ying,Gao, Li-Xin,Jin, Yi,et al. 4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2014,22(14):3670-3683.
APA	Zhi, Ying.,Gao, Li-Xin.,Jin, Yi.,Tang, Chun-Lan.,Li, Jing-Ya.,...&Long, Ya-Qiu.(2014).4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B.BIOORGANIC & MEDICINAL CHEMISTRY,22(14),3670-3683.
MLA	Zhi, Ying,et al."4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B".BIOORGANIC & MEDICINAL CHEMISTRY 22.14(2014):3670-3683.