title: Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors.
abstract: Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. athomas@arraybiopharma.com
authors.forename: Allen A
authors.initials: AA
authors.lastname: Thomas
authors.forename: Y
authors.initials: Y
authors.lastname: Le Huerou
authors.forename: J
authors.initials: J
authors.lastname: De Meese
authors.forename: Indrani
authors.initials: I
authors.lastname: Gunawardana
authors.forename: Tomas
authors.initials: T
authors.lastname: Kaplan
authors.forename: Todd T
authors.initials: TT
authors.lastname: Romoff
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Gonzales
authors.forename: Kevin
authors.initials: K
authors.lastname: Condroski
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.forename: Josh
authors.initials: J
authors.lastname: Ballard
authors.forename: Bryan
authors.initials: B
authors.lastname: Bernat
authors.forename: Walter
authors.initials: W
authors.lastname: DeWolf
authors.forename: May
authors.initials: M
authors.lastname: Han
authors.forename: Patrice
authors.initials: P
authors.lastname: Lee
authors.forename: Christine
authors.initials: C
authors.lastname: Lemieux
authors.forename: Robin
authors.initials: R
authors.lastname: Pedersen
authors.forename: Jed
authors.initials: J
authors.lastname: Pheneger
authors.forename: Greg
authors.initials: G
authors.lastname: Poch
authors.forename: Darin
authors.initials: D
authors.lastname: Smith
authors.forename: Francis
authors.initials: F
authors.lastname: Sullivan
authors.forename: Solly
authors.initials: S
authors.lastname: Weiler
authors.forename: S Kirk
authors.initials: SK
authors.lastname: Wright
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Barb
authors.initials: B
authors.lastname: Brandhuber
authors.forename: Guy
authors.initials: G
authors.lastname: Vigers
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010119:Oxythiamine / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013831:Thiamine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D014174:Transketolase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D010119:Oxythiamine; D005954:Glucosephosphate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D014174:Transketolase; D013831:Thiamine