title: Non-charged thiamine analogs as inhibitors of enzyme transketolase.
abstract: Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.
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: J
authors.initials: J
authors.lastname: De Meese
authors.forename: Y
authors.initials: Y
authors.lastname: Le Huerou
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.forename: Todd T
authors.initials: TT
authors.lastname: Romoff
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gonzales
authors.forename: Indrani
authors.initials: I
authors.lastname: Gunawardana
authors.forename: Tomas
authors.initials: T
authors.lastname: Kaplan
authors.forename: Francis
authors.initials: F
authors.lastname: Sullivan
authors.forename: Kevin
authors.initials: K
authors.lastname: Condroski
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
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: Christine
authors.initials: C
authors.lastname: Lemieux
authors.forename: Darin
authors.initials: D
authors.lastname: Smith
authors.forename: Solly
authors.initials: S
authors.lastname: Weiler
authors.forename: S Kirk
authors.initials: SK
authors.lastname: Wright
authors.forename: Guy
authors.initials: G
authors.lastname: Vigers
authors.forename: Barb
authors.initials: B
authors.lastname: Brandhuber
mesh_terms: D000818:Animals; D002384:Catalysis; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013831:Thiamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014174:Transketolase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D014174:Transketolase; D013831:Thiamine