Evaluation of Thieno[3,2-b]pyrrole[3,2-d]pyridazinones As Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2010 May 11

PMID 20451379

Citations 46

Authors

Jian-Kang Jiang

Matthew B Boxer

Matthew G Vander Heiden

Min Shen

Amanda P Skoumbourdis

Noel Southall

Henrike Veith

William Leister

Christopher P Austin

Hee Won Park

James Inglese

Lewis C Cantley

Douglas S Auld

Craig J Thomas

Affiliations

Soon will be listed here.

Abstract

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.

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References

Takenaka M, Yamada K, Lu T, Kang R, Tanaka T, Noguchi T . Alternative splicing of the pyruvate kinase M gene in a minigene system. Eur J Biochem. 1996; 235(1-2):366-71. DOI: 10.1111/j.1432-1033.1996.00366.x. View

Christofk H, Vander Heiden M, Harris M, Ramanathan A, Gerszten R, Wei R . The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452(7184):230-3. DOI: 10.1038/nature06734. View

DeBerardinis R, Lum J, Hatzivassiliou G, Thompson C . The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008; 7(1):11-20. DOI: 10.1016/j.cmet.2007.10.002. View

Chabert J, Marquez B, Neville L, Joucla L, Broussous S, Bouhours P . Synthesis and evaluation of new arylbenzo[b]thiophene and diarylthiophene derivatives as inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Bioorg Med Chem. 2007; 15(13):4482-97. DOI: 10.1016/j.bmc.2007.04.023. View

Eigenbrodt E, Basenau D, Holthusen S, Mazurek S, Fischer G . Quantification of tumor type M2 pyruvate kinase (Tu M2-PK) in human carcinomas. Anticancer Res. 1997; 17(4B):3153-6. View

Mazurek S, Boschek C, Hugo F, Eigenbrodt E . Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005; 15(4):300-8. DOI: 10.1016/j.semcancer.2005.04.009. View

Reinacher M, Eigenbrodt E . Immunohistological demonstration of the same type of pyruvate kinase isoenzyme (M2-Pk) in tumors of chicken and rat. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981; 37(1):79-88. DOI: 10.1007/BF02892557. View

Warburg O . On respiratory impairment in cancer cells. Science. 1956; 124(3215):269-70. View

Frere P, Raimundo J, Blanchard P, Delaunay J, Richomme P, Sauvajol J . Effect of local molecular structure on the chain-length dependence of the electronic properties of thiophene-based pi-conjugated systems. J Org Chem. 2003; 68(19):7254-65. DOI: 10.1021/jo034319o. View

10.

Hannaert V, Yernaux C, Rigden D, Fothergill-Gilmore L, Opperdoes F, Michels P . The putative effector-binding site of Leishmania mexicana pyruvate kinase studied by site-directed mutagenesis. FEBS Lett. 2002; 514(2-3):255-9. DOI: 10.1016/s0014-5793(02)02374-8. View

11.

Wang X, Sun X, Zhang L, Xu Y, Krishnamurthy D, Senanayake C . Noncryogenic I/Br-Mg exchange of aromatic halides bearing sensitive functional groups using i-PrMgCl-bis[2-(N,N-dimethylamino)ethyl] ether complexes. Org Lett. 2006; 8(2):305-7. DOI: 10.1021/ol052704p. View

12.

Takenaka M, Noguchi T, Sadahiro S, Hirai H, Yamada K, Matsuda T . Isolation and characterization of the human pyruvate kinase M gene. Eur J Biochem. 1991; 198(1):101-6. DOI: 10.1111/j.1432-1033.1991.tb15991.x. View

13.

Singh P, Harden B, Lillywhite B, Broad P . Identification of kinase inhibitors by an ATP depletion method. Assay Drug Dev Technol. 2004; 2(2):161-9. DOI: 10.1089/154065804323056503. View

14.

Klapars A, Antilla J, Huang X, Buchwald S . A general and efficient copper catalyst for the amidation of aryl halides and the N-arylation of nitrogen heterocycles. J Am Chem Soc. 2001; 123(31):7727-9. DOI: 10.1021/ja016226z. View

15.

Christofk H, Vander Heiden M, Wu N, Asara J, Cantley L . Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008; 452(7184):181-6. DOI: 10.1038/nature06667. View

16.

Noguchi T, Yamada K, Inoue H, Matsuda T, Tanaka T . The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J Biol Chem. 1987; 262(29):14366-71. View

17.

Dombrauckas J, Santarsiero B, Mesecar A . Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry. 2005; 44(27):9417-29. DOI: 10.1021/bi0474923. View

18.

Pandey A, Volkots D, Seroogy J, Rose J, Yu J, Lambing J . Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem. 2002; 45(17):3772-93. DOI: 10.1021/jm020143r. View

19.

Vander Heiden M, Cantley L, Thompson C . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324(5930):1029-33. PMC: 2849637. DOI: 10.1126/science.1160809. View

20.

Inglese J, Auld D, Jadhav A, Johnson R, Simeonov A, Yasgar A . Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci U S A. 2006; 103(31):11473-8. PMC: 1518803. DOI: 10.1073/pnas.0604348103. View