Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors.
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.
Thomas
Allen A
AA
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. athomas@arraybiopharma.com
Le Huerou
Y
Y
De Meese
J
J
Gunawardana
Indrani
I
Kaplan
Tomas
T
Romoff
Todd T
TT
Gonzales
Stephen S
SS
Condroski
Kevin
K
Boyd
Steven A
SA
Ballard
Josh
J
Bernat
Bryan
B
DeWolf
Walter
W
Han
May
M
Lee
Patrice
P
Lemieux
Christine
C
Pedersen
Robin
R
Pheneger
Jed
J
Poch
Greg
G
Smith
Darin
D
Sullivan
Francis
F
Weiler
Solly
S
Wright
S Kirk
SK
Lin
Jie
J
Brandhuber
Barb
B
Vigers
Guy
G
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
D004791:Enzyme Inhibitors; D010119:Oxythiamine; D005954:Glucosephosphate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D014174:Transketolase; D013831:Thiamine