biostudies-literatureMilano SKScience and Engineering Research BoardCanterbury Medical Research FoundationNCI NIH HHSNIHNIGMS NIH HHS101535https://www.ebi.ac.uk/biostudies/studies/S-EPMC8784640biostudies-literatureUnknown298(2)Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e., the "Warburg effect") and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this 'glutamine addiction' of cancer cells by catalyzing the hydrolysis of glutamine to glutamate, which is then converted to the TCA-cycle intermediate α-ketoglutarate. This makes GAC an intriguing drug target and spurred the molecules derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (the so-called BPTES class of allosteric GAC inhibitors), including CB-839, which is currently in clinical trials. However, none of the drugs targeting GAC are yet approved for cancer treatment and their mechanism of acThe Journal of biological chemistryNew insights into the molecular mechanisms of glutaminase C inhibitors in cancer cells using serial room temperature crystallography.PMC8784640GM122575R35 GM122575EMR/2016-002141P30GM126166R01 CA201402Ramachandran SFinke AMcDermott LASukumar NKriksunov IHuang QSchuller DJSzebenyi DMCerione RANguyen TTKatt WPMilano SKArenholz EfalseNew insights into the molecular mechanisms of glutaminase C inhibitors in cancer cells using serial room temperature crystallography.Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e., the "Warburg effect") and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this 'glutamine addiction' of cancer cells by catalyzing the hydrolysis of glutamine to glutamate, which is then converted to the TCA-cycle intermediate α-ketoglutarate. This makes GAC an intriguing drug target and spurred the molecules derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (the so-called BPTES class of allosteric GAC inhibitors), including CB-839, which is currently in clinical trials. However, none of the drugs targeting GAC are yet approved for cancer treatment and their mechanism of ac2022-01-01T00:00:00Z2022 Feb2026-05-09T02:27:57.514Z2022-02-11T15:40:58.442ZS-EPMC87846403495414310.1016/j.jbc.2021.101535