Diselenide Covalent Allosteric Inhibitors of Glutaminase with Strong In Vivo Anticancer Activity.

ABSTRACT: Allosteric glutaminase inhibitors demonstrate inhibition of glutamine-dependent cancer cells with low general drug toxicity, but have issues with efficacy in vivo. Here, we designed a series of diselenide compounds with 6 atoms in the middle, aiming to target the allosteric site of kidney type glutaminase (KGA) with a covalent linkage to strengthen the interaction. Proteomic analysis demonstrated that the diselenide compounds cross-linked with the Lys320 residue at the KGA allosteric site; this was confirmed by the KGA K320A mutant which showed essentially no binding to the diselenide. Further, structure-activity relationship (SAR) analysis demonstrated that growth inhibition correlated well with KGA inhibition and was enhanced by thioredoxin reductase (TrxR) inhibition. Interesting

SUBMITTER: Hou W 

PROVIDER: S-EPMC10351061 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature