Allen A Thomas,
Y Le Huerou,
J De Meese,
Indrani Gunawardana,
Tomas Kaplan,
Todd T Romoff,
Stephen S Gonzales,
Kevin Condroski,
Steven A Boyd,
Josh Ballard, [......],
Robin Pedersen,
Jed Pheneger, Greg Poch,
Darin Smith,
Francis Sullivan,
Solly Weiler,
S Kirk Wright,
Jie Lin,
Barb Brandhuber,
Guy Vigers
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):2206-10. · 2.65 Impact Factor
