Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase

被引：96

作者：

Jiang, Jian-kang ^{[1
]}

Boxer, Matthew B. ^{[1
]}

Vander Heiden, Matthew G. ^{[2
,3
,4
]}

Shen, Min ^{[1
]}

Skoumbourdis, Amanda P. ^{[1
]}

Southall, Noel ^{[1
]}

Veith, Henrike ^{[1
]}

Leister, William ^{[1
]}

Austin, Christopher P. ^{[1
]}

Park, Hee Won ^{[5
,6
]}

Inglese, James ^{[1
]}

Cantley, Lewis C. ^{[3
,7
]}

Auld, Douglas S. ^{[1
]}

Thomas, Craig J. ^{[1
]}

机构：

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

[2] MIT, Robert Koch Inst, Cambridge, MA 02139 USA

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

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

[5] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L5, Canada

[6] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 11期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

Warburg effect; Pyruvate kinase; Cellular metabolism; Anti-cancer strategies; Small molecule activators; CANCER CELLS; M-GENE; GROWTH; RAT; IDENTIFICATION; METABOLISM; INHIBITORS; ISOZYMES; HALIDES; M2-PK;

D O I：

10.1016/j.bmcl.2010.04.015

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cancer cells have distinct metabolic needs that are different from normal cells and can be exploited for development of anti-cancer therapeutics. Activation of the tumor specific M2 form of pyruvate kinase (PKM2) is a potential strategy for returning cancer cells to a metabolic state characteristic of normal cells. Here, we describe activators of PKM2 based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold. The synthesis of these agents, structure-activity relationships, analysis of activity at related targets (PKM1, PKR and PKL) and examination of aqueous solubility are investigated. These agents represent the second reported chemotype for activation of PKM2. Published by Elsevier Ltd.

引用

页码：3387 / 3393

页数：7

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