Novel 1,3,4-Selenadiazole-Containing Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity

Kidney-type glutaminase [KGA/isoenzyme
glutaminase C (GAC)] is
becoming an important tumor metabolism target in cancer chemotherapy.
Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics
but limited efficacy in in vivo cancer models. To improve the in vivo
activity, we explored a bioisostere replacement of the sulfur atom
in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)­ethyl sulfide and CB839
analogues with selenium using a novel synthesis of the selenadiazole
moiety from carboxylic acids or nitriles. The resulting selenadiazole
compounds showed enhanced KGA inhibition, more potent induction of
reactive oxygen species, improved inhibition of cancer cells, and
higher cellular and tumor accumulation than the corresponding sulfur-containing
molecules. However, both CB839 and its selenium analogues show incomplete
inhibition of the tested cancer cells, and a partial reduction in
tumor size was observed in both the glutamine-dependent HCT116 and
aggressive H22 liver cancer xenograft models. Despite this, tumor
tissue damage and prolonged survival were observed in animals treated
with the selenium analogue of CB839.