Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Labadie, Sharada¹  Dragovich, Peter S.¹  Chen, Jinhua²  Fauber, Benjamin P.¹  Boggs, Jason¹  Corson, Laura B.¹  Ding, Charles Z.²  Eigenbrot, Charles¹  Ge, HongXiu²  Ho, Qunh²  Lai, Kwong Wah²  Ma, Shuguang¹  Malek, Shiva¹  Peterson, David¹  Purkey, Hans E.¹  Robarge, Kirk¹  Salphati, Laurent¹  Sideris, Steven¹  Ultsch, Mark¹  VanderPorten, Erica¹  Wei, BinQing¹  Xu, Qing²  Yen, Ivana¹  Yue, Qin¹  Zhang, Huihui²  Zhang, Xuying²  Zhou, Aihe¹ 

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

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

关键词: Lactate dehydrogenase A;    Glycolysis;    Tumor metabolism;    Structure-based design;   

DOI  :  10.1016/j.bmcl.2014.11.008

来源: Elsevier

【 摘 要 】

Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4-10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency. (C) 2014 Elsevier Ltd. All rights reserved.

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