Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors

被引：141

作者：

Lee, Kyungik ^{[2
,3
]}

Jeong, Ki-Woong ^{[1
]}

Lee, Yeonjoo ^{[2
]}

Song, Ji Yeon ^{[2
]}

Kim, Maeng Sup ^{[2
]}

Lee, Gwan Sun ^{[2
]}

Kim, Yangmee ^{[1
]}

机构：

[1] Konkuk Univ, Dept Biosci & Biotechnol, Seoul 143701, South Korea

[2] Hanmi Pharmaceut Co Ltd, Hanmi Res Ctr, Hwaseong Si 445813, Gyeonggi Do, South Korea

[3] Konkuk Univ, Dept Chem, Seoul 143701, South Korea

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 11期

基金：

新加坡国家研究基金会;

关键词：

VEGFR-2; Virtual screening; Docking; Anticancer activity; Kinase inhibitor; ENDOTHELIAL GROWTH-FACTOR; RECEPTOR TYROSINE KINASES; SCORING FUNCTIONS; ANGIOGENESIS; PERMEABILITY; DISCOVERY; TARGETS; CANCER;

D O I：

10.1016/j.ejmech.2010.09.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Virtual screening was performed to determine potent vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitors. A database of approximately 820,000 commercial compounds was used for screening, and 100 compounds were chosen as candidate VEGFR-2 inhibitors through pharmacophore modeling and docking studies. These 100 compounds were purchased to test their biological activities: 10 compounds were found to inhibit the enzyme, with IC50 values ranging from 10 to 1 mu M. Compound 1, which has a triazinoindole ring, inhibited the enzymatic activity of VEGFR-2, with an IC50 value of about 1.6 mu M, making it the most potent inhibitor of this enzyme. The triazinoindole derivative may therefore serve as the starting point in the design of new VEGFR-2 kinase inhibitors. (C) 2010 Elsevier Masson SAS. All rights reserved.

引用

页码：5420 / 5427

页数：8

共 34 条

[1]

*ACC INC, DS MOD 1 7 CERIUS2 L

[2] Kinase inhibition with BAY 43-9006 n renal cell carcinoma [J].

Ahmad, T ;

Eisen, T .

CLINICAL CANCER RESEARCH, 2004, 10 (18) :6388S-6392S

[3] Computational methods to predict binding free energy in ligand-receptor complexes [J].

Ajay ;

Murcko, MA .

JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (26) :4953-4967

[4] AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients [J].

Batchelor, Tracy T. ;

Sorensen, A. Gregory ;

di Tomaso, Emmanuelle ;

Zhang, Wei-Ting ;

Duda, Dan G. ;

Cohen, Kenneth S. ;

Kozak, Kevin R. ;

Cahill, Daniel P. ;

Chen, Poe-Jou ;

Zhu, Mingwang ;

Ancukiewicz, Marek ;

Mrugala, Maciej M. ;

Plotkin, Scott ;

Drappatz, Jan ;

Louis, David N. ;

Ivy, Percy ;

Scadden, David T. ;

Benner, Thomas ;

Loeffler, Jay S. ;

Wen, Patrick Y. ;

Jain, Rakesh K. .

CANCER CELL, 2007, 11 (01) :83-95

[5] Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations [J].

Bissantz, C ;

Folkers, G ;

Rognan, D .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (25) :4759-4767

[6]

Boyer Stephen J., 2002, Current Topics in Medicinal Chemistry, V2, P973, DOI 10.2174/1568026023393273

[7] TIVOZANIB VEGFR Tyrosine Kinase Inhibitor Angiogenesis Inhibitor Oncolytic [J].

Campas, C. ;

Bolos, J. ;

Castaner, R. .

DRUGS OF THE FUTURE, 2009, 34 (10) :793-796

[8] Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study [J].

Cohen, Ezra E. W. ;

Rosen, Lee S. ;

Vokes, Everett E. ;

Kies, Merrill S. ;

Forastiere, Arlene A. ;

Worden, Francis P. ;

Kane, Madeleine A. ;

Sherman, Eric ;

Kim, Sinil ;

Bycott, Paul ;

Tortorici, Michael ;

Shalinsky, David R. ;

Liau, Katherine F. ;

Cohen, Roger B. .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (29) :4708-4713

[9] THE FMS-LIKE TYROSINE KINASE, A RECEPTOR FOR VASCULAR ENDOTHELIAL GROWTH-FACTOR [J].

DEVRIES, C ;

ESCOBEDO, JA ;

UENO, H ;

HOUCK, K ;

FERRARA, N ;

WILLIAMS, LT .

SCIENCE, 1992, 255 (5047) :989-991

[10] Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy [J].

Dvorak, HF .

JOURNAL OF CLINICAL ONCOLOGY, 2002, 20 (21) :4368-4380

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