Discovery of novel fatty acid synthase (FAS) inhibitors based on the structure of ketoaceyl synthase (KS) domain

被引：16

作者：

Zeng, Xiao-Fei ^{[2
,3
]}

Li, Wei-Wei ^{[2
,3
]}

Fan, Hui-Jin ^{[1
]}

Wang, Xiao-Yan ^{[2
,3
]}

Ji, Pan ^{[2
,3
]}

Wang, Ze-Rong ^{[2
,3
]}

Ma, Shuang ^{[2
,3
]}

Li, Lin-Li ^{[2
,3
]}

Ma, Xiao-Feng ^{[1
]}

Yang, Sheng-Yong ^{[2
,3
]}

机构：

[1] Chinese Acad Sci, Coll Life Sci, Grad Univ, Beijing 100049, Peoples R China

[2] Sichuan Univ, State Key Lab Biotherapy, W China Hosp, W China Med Sch, Chengdu 610041, Sichuan, Peoples R China

[3] Sichuan Univ, Ctr Canc, W China Hosp, W China Med Sch, Chengdu 610041, Sichuan, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 16期

基金：

中国国家自然科学基金;

关键词：

Fatty acid synthase (FAS); Ketoaceyl synthase (KS) domain; Structure-based pharmacophore modeling; Docking; BREAST-CARCINOMA PATIENTS; CANCER-CELLS; PROSTATE-CANCER; EXPRESSION; APOPTOSIS; TARGET;

D O I：

10.1016/j.bmcl.2011.06.075

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4742 / 4744

页数：3

共 28 条

[1]

Alo PL, 1996, CANCER, V77, P474, DOI 10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO

[2]

2-K

[3] FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis [J].

Bandyopadhyay, S ;

Pai, SK ;

Watabe, M ;

Gross, SC ;

Hirota, S ;

Hosobe, S ;

Tsukada, T ;

Miura, K ;

Saito, K ;

Markwell, SJ ;

Wang, Y ;

Huggenvik, J ;

Pauza, ME ;

Iiizumi, M ;

Watabe, K .

ONCOGENE, 2005, 24 (34) :5389-5395

[4] Fatty acid synthase gene expression in human adipose tissue:: association with obesity and type 2 diabetes [J].

Berndt, J. ;

Kovacs, P. ;

Ruschke, K. ;

Kloeting, N. ;

Fasshauer, M. ;

Schoen, M. R. ;

Koerner, A. ;

Stumvoll, M. ;

Blueher, M. .

DIABETOLOGIA, 2007, 50 (07) :1472-1480

[5]

Gabrielson EW, 2001, CLIN CANCER RES, V7, P153

[6]

GUNTER P, 2010, J MOL BIOL, V397, P508

[7]

Huang PL, 2000, WORLD J GASTROENTERO, V6, P295

[8]

KIM K, 2002, AM J PHYSIOL-ENDOC M, V283, pE867

[9] Synthesis and antitumor activity of an inhibitor of fatty acid synthase [J].

Kuhajda, FP ;

Pizer, ES ;

Li, JN ;

Mani, NS ;

Frehywot, GL ;

Townsend, CA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (07) :3450-3454

[10] Fatty-acid synthase and human cancer: New perspectives on its role in tumor biology [J].

Kuhajda, FP .

NUTRITION, 2000, 16 (03) :202-208

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