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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Jiang, Jian-kang¹  Boxer, Matthew B.¹  Vander Heiden, Matthew G.^2,3,4  Shen, Min¹  Skoumbourdis, Amanda P.¹  Southall, Noel¹  Veith, Henrike¹  Leister, William¹  Austin, Christopher P.¹  Park, Hee Won^5,6  Inglese, James¹  Cantley, Lewis C.^3,7  Auld, Douglas S.¹  Thomas, Craig J.¹ 

[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

关键词: Warburg effect;    Pyruvate kinase;    Cellular metabolism;    Anti-cancer strategies;    Small molecule activators;   

DOI  :  10.1016/j.bmcl.2010.04.015

来源: Elsevier

【 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.

【 授权许可】

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