title: 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase.
abstract: 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.
authors.affiliation: NIH Chemical Genomics Center, NIH Center for Translational Therapeutics, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.forename: Henrike
authors.initials: H
authors.lastname: Veith
authors.forename: James M
authors.initials: JM
authors.lastname: Bougie
authors.forename: Thomas
authors.initials: T
authors.lastname: Daniel
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: William J
authors.initials: WJ
authors.lastname: Israelsen
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
mesh_terms: D017398:Alternative Splicing; D018938:Caco-2 Cells; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D011770:Pyruvate Kinase / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D020536:Enzyme Activators; D007527:Isoenzymes; D011804:Quinolines; C542964:1,2,3,4-tetrahydroquinoline; D011770:Pyruvate Kinase