Selective, orally bioavailable allosteric inhibitor of glutaminase (GLS, both KGA and GAC isoforms). Blocks the conversion of glutamine to glutamate at the inner mitochondrial membrane. In SDH-deficient cells, TCA cycle truncation at the succinate→fumarate step forces a shift to reductive glutamine carboxylation as the dominant citrate-forming pathway: GLS converts glutamine to glutamate → α-ketoglutarate (α-KG), which reverse NADPH-dependent IDH2 then converts to isocitrate and citrate — providing acetyl-CoA for lipid synthesis and replenishing four-carbon anaplerotic intermediates without requiring functional Complex II (Mullen et al., Nature 2012, PMID 22101431). GLS is the committed entry step for this reductive flux; its inhibition more severely depletes citrate, acetyl-CoA, and proliferative capacity in SDH-deficient cells than in SDH-intact cells with intact oxidative TCA cycling. Separately, Lussey-Lepoutre et al. (Nat Commun 2015, PMID 26522426) demonstrated in SDH-deficient paraganglioma models that TCA truncation forces broad compensatory metabolic reprogramming including anaplerotic dependencies not present in SDH-intact cells, confirming this metabolic vulnerability class. CB-839 has been evaluated in the CANTATA (NCT03428217) and ENTRATA (NCT02071862) Phase 2 trials; no SDH-genotype-stratified efficacy data have been reported.