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Beschreibung

A cell-permeable bis-thiadiazole compound that selectively inhibits GLS1 (IC50 = 60 and 80 nM, respectively, against hKGA and hGAC), but not the liver-type GLS2/LGA (IC50 = 88 µ,M using hLGA), mitochondrial glutaminase (GA) activity by inducing an inactive GLS1 tetrameric conformation via a 2:1 inhibitor-to-tetramer stoichiometric binding, non-competitive against glutamine or phosphate binding. B-cell lymphoma line P493 is shown to depend primarily on glutamine metabolism for survival under hypoxic condition and cellular GLS1 inhibtion by BPTES treatment results in cell death (2 µ,M BPTES & 3% O2 for 4 d), while under aerobic/normoxic condition (20% O2 and up to 10 µ,M BPTES for 4 d) only growth inhibition is observed. Likewise, intraperitoneal administration (12.5 mg/kg or 200 µ,g/animal, q.o.d.) is demonstrated to be efficacious in suppressing P493 tumor expansion in mice in vivo., A cell-permeable bis-thiadiazole compound that selectively inhibits GLS1 (IC50 = 60 and 80 nM, respectively, against hKGA and hGAC), but not the liver-type GLS2/LGA (IC50 = 88 µ,M using hLGA) mitochondrial glutaminase (GA) activity by inducing an inactive GLS1 tetrameric conformation via a 2:1 inhibitor-to-tetramer stoichiometric binding. Shown to induce growth inhibition under aerobic/normoxic (up to 10 µ,M, 20% O2) and cell death under hypoxic (2 µ,M, 3% O2) in P493 B-cell lymphoma cultures in vitro and effectively suppress P493 tumor expansion in mice in vivo (12.5 mg/kg or 200 µ,g/animal via i.p., q.o.d.).