Discovery of 2-((1H-benzo[d]imidazol-1-yl) methyl)-4H-pyrido [1,2-a]pyrimidin-4-ones as novel PKM2 activators

被引：38

作者：

Guo, Chuangxing ^{[1
]}

Linton, Angelica ^{[1
]}

Jalaie, Mehran ^{[1
]}

Kephart, Susan ^{[1
]}

Ornelas, Martha ^{[1
]}

Pairish, Mason ^{[1
]}

Greasley, Samantha ^{[1
]}

Richardson, Paul ^{[1
]}

Maegley, Karen ^{[1
]}

Hickey, Michael ^{[1
]}

Li, John ^{[1
]}

Wu, Xin ^{[1
]}

Ji, Xiaodong ^{[1
]}

Xie, Zhi ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Oncol Med Chem, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 11期

关键词：

M2 isoform of pyruvate kinase; PKM2; activator; activation; PKM1; Cancer metabolism; Warburg effect; Anti-tumor; Anti-cancer; PYRUVATE-KINASE M2; ISOFORM; METABOLISM; DESIGN;

D O I：

10.1016/j.bmcl.2013.03.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：3358 / 3363

页数：6

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