Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase

被引：53

作者：

Fauber, Benjamin P. ^{[1
]}

Dragovich, Peter S. ^{[1
]}

Chen, Jinhua ^{[2
]}

Corson, Laura B. ^{[1
]}

Ding, Charles Z. ^{[2
]}

Eigenbrot, Charles ^{[1
]}

Giannetti, Anthony M. ^{[1
]}

Hunsaker, Thomas ^{[1
]}

Labadie, Sharada ^{[1
]}

Liu, Yichin ^{[1
]}

Liu, Yingchun ^{[2
]}

Malek, Shiva ^{[1
]}

Peterson, David ^{[1
]}

Pitts, Keith ^{[1
]}

Sideris, Steve ^{[1
]}

Ultsch, Mark ^{[1
]}

VanderPorten, Erica ^{[1
]}

Wang, Jing ^{[2
]}

Wei, BinQing ^{[1
]}

Yen, Ivana ^{[1
]}

Yue, Qin ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] WuXi AppTec Co Ltd, Shanghai 200131, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 20期

关键词：

Lactate dehydrogenase; X-ray crystal structure; Pyrazine; Tumor metabolism; LEAD; DEFICIENCY; ISOZYME;

D O I：

10.1016/j.bmcl.2013.08.060

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A 2-amino-5-aryl-pyrazine was identified as an inhibitor of human lactate dehydrogenase A (LDHA) via a biochemical screening campaign. Biochemical and biophysical experiments demonstrated that the compound specifically interacted with human LDHA. Structural variation of the screening hit resulted in improvements in LDHA biochemical inhibition and pharmacokinetic properties. A crystal structure of an improved compound bound to human LDHA was also obtained and it explained many of the observed structure-activity relationships. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：5533 / 5539

页数：7

共 37 条

[1]

BALINSKY D, 1983, CANCER RES, V43, P5895

[2]

Billiard J., 2013, J AM ASS CANC RES

[3]

Brown K.K., 2013, [No title captured], Patent No. [WO2013/096151, 2013096151]

[4]

Chai D., 2012, Patent WO, Patent No. [WO2012/061557, 2012061557, 2012061557 A3]

[5] Structure of lactate dehydrogenase from Plasmodium vivax:: Complexes with NADH and APADH [J].

Chaikuad, A ;

Fairweather, V ;

Conners, R ;

Joseph-Horne, T ;

Turgut-Balik, D ;

Brady, RL .

BIOCHEMISTRY, 2005, 44 (49) :16221-16228

[6]

Chianelli D., 2010, [No title captured], Patent No. [WO2010/127152, 2010127152]

[7] GENOMIC ORGANIZATION OF HUMAN LACTATE DEHYDROGENASE-A GENE [J].

CHUNG, FZ ;

TSUJIBO, H ;

BHATTACHARYYA, U ;

SHARIEF, FS ;

LI, SSL .

BIOCHEMICAL JOURNAL, 1985, 231 (03) :537-541

[8] Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK) [J].

Cui, J. Jean ;

Tran-Dube, Michelle ;

Shen, Hong ;

Nambu, Mitchell ;

Kung, Pei-Pei ;

Pairish, Mason ;

Jia, Lei ;

Meng, Jerry ;

Funk, Lee ;

Botrous, Iriny ;

McTigue, Michele ;

Grodsky, Neil ;

Ryan, Kevin ;

Padrique, Ellen ;

Alton, Gordon ;

Timofeevski, Sergei ;

Yamazaki, Shinji ;

Li, Quhua ;

Zou, Helen ;

Christensen, James ;

Mroczkowski, Barbara ;

Bender, Steve ;

Kania, Robert S. ;

Edwards, Martin P. .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (18) :6342-6363

[9] Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase [J].

Dragovich, Peter S. ;

Fauber, Benjamin P. ;

Corson, Laura B. ;

Ding, Charles Z. ;

Eigenbrot, Charles ;

Ge, HongXiu ;

Giannetti, Anthony M. ;

Hunsaker, Thomas ;

Labadie, Sharada ;

Liu, Yichin ;

Malek, Shiva ;

Pan, Borlan ;

Peterson, David ;

Pitts, Keith ;

Purkey, Hans E. ;

Sideris, Steve ;

Ultsch, Mark ;

VanderPorten, Erica ;

Wei, BinQing ;

Xu, Qing ;

Yen, Ivana ;

Yue, Qin ;

Zhang, Huihui ;

Zhang, Xuying .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (11) :3186-3194

[10] Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance [J].

Fantin, Valeria R. ;

St-Pierre, Julie ;

Leder, Philip .

CANCER CELL, 2006, 9 (06) :425-434

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