2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase

被引：51

作者：

Walsh, Martin J. ^{[1
]}

Brimacombe, Kyle R. ^{[1
]}

Veith, Henrike ^{[1
]}

Bougie, James M. ^{[1
]}

Daniel, Thomas ^{[1
]}

Leister, William ^{[1
]}

Cantley, Lewis C. ^{[2
,3
]}

Israelsen, William J. ^{[4
]}

Vander Heiden, Matthew G. ^{[4
,5
]}

Shen, Min ^{[1
]}

Auld, Douglas S. ^{[1
]}

Thomas, Craig J. ^{[1
]}

Boxer, Matthew B. ^{[1
]}

机构：

[1] NHGRI, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, NIH, Rockville, MD 20850 USA

[2] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[4] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[5] Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

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

基金：

美国国家卫生研究院;

关键词：

PKM2; Pyruvate kinase; Cellular metabolism; Anti-cancer strategies; Small molecule activators; GENE; RAT; ISOZYMES; GROWTH; SYSTEM;

D O I：

10.1016/j.bmcl.2011.08.114

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. Published by Elsevier Ltd.

引用

页码：6322 / 6327

页数：6