title: Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase.
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.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Jian-kang
authors.initials: JK
authors.lastname: Jiang
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Skoumbourdis
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Henrike
authors.initials: H
authors.lastname: Veith
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Hee Won
authors.initials: HW
authors.lastname: Park
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
mesh_terms: D020536:Enzyme Activators / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D011770:Pyruvate Kinase / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D007527:Isoenzymes; D011724:Pyridazines; D011770:Pyruvate Kinase
references.citation: Eur J Biochem. 1996 Jan 15;235(1-2):366-71
references.pmid: 8631356
references.citation: Nature. 2008 Mar 13;452(7184):230-3
references.pmid: 18337823
references.citation: Cell Metab. 2008 Jan;7(1):11-20
references.pmid: 18177721
references.citation: Bioorg Med Chem. 2007 Jul 1;15(13):4482-97
references.pmid: 17498961
references.citation: Anticancer Res. 1997 Jul-Aug;17(4B):3153-6
references.pmid: 9329624
references.citation: Semin Cancer Biol. 2005 Aug;15(4):300-8
references.pmid: 15908230
references.citation: Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;37(1):79-88
references.pmid: 6116351
references.citation: Science. 1956 Aug 10;124(3215):269-70
references.pmid: 13351639
references.citation: J Org Chem. 2003 Sep 19;68(19):7254-65
references.pmid: 12968874
references.citation: FEBS Lett. 2002 Mar 13;514(2-3):255-9
references.pmid: 11943161
references.citation: Org Lett. 2006 Jan 19;8(2):305-7
references.pmid: 16408901
references.citation: Eur J Biochem. 1991 May 23;198(1):101-6
references.pmid: 2040271
references.citation: Assay Drug Dev Technol. 2004 Apr;2(2):161-9
references.pmid: 15165512
references.citation: J Am Chem Soc. 2001 Aug 8;123(31):7727-9
references.pmid: 11481007
references.citation: Nature. 2008 Mar 13;452(7184):181-6
references.pmid: 18337815
references.citation: J Biol Chem. 1987 Oct 15;262(29):14366-71
references.pmid: 3654663
references.citation: Biochemistry. 2005 Jul 12;44(27):9417-29
references.pmid: 15996096
references.citation: J Med Chem. 2002 Aug 15;45(17):3772-93
references.pmid: 12166950
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8
references.pmid: 16864780
references.citation: Virchows Arch. 1999 Mar;434(3):213-20
references.pmid: 10190300
references.citation: J Med Chem. 2010 Feb 11;53(3):1048-55
references.pmid: 20017496
references.citation: Curr Opin Genet Dev. 2008 Feb;18(1):54-61
references.pmid: 18387799
references.citation: J Org Chem. 2005 Oct 28;70(22):9077-80
references.pmid: 16238359
references.citation: J Biol Chem. 1986 Oct 15;261(29):13807-12
references.pmid: 3020052
references.citation: Biochem Biophys Res Commun. 1999 Mar 16;256(2):257-62
references.pmid: 10079172
references.citation: Assay Drug Dev Technol. 2007 Feb;5(1):127-36
references.pmid: 17355205
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683