Sun, Weiguang published the artcileAspulvinone O, a natural inhibitor of GOT1 suppresses pancreatic ductal adenocarcinoma cells growth by interfering glutamine metabolism, Safety of (S)-2-hydroxysuccinic acid, the main research area is aspulvinone O antitumor GOT1 inhibitor glutamine pancreatic ductal adenocarcinoma; Aspulvinone O; GOT1 inhibitor; Glutamine metabolism; Pancreatic ductal adenocarcinoma cells.
Background: Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate transaminase 1 (GOT1) to rewire glutamine metabolism and support NADP (NADPH) production Thus, the important role of GOT1 in energy metabolism and Reactive Oxygen Species (ROS) balance demonstrates that targeting GOT1 may serve as an important therapeutic target in PDAC. Methods: To assay the binding affinity between Aspulvinone O (AO) and GOT1 proteins, the virtual docking, microscale thermophoresis (MST), cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) methods were employed. GOT1 was silenced in several PDAC cell lines. The level of OCR and ECR were assayed by seahorse. To evaluate the in vivo anti-tumor efficacy of AO, the xenograft model was built in CB17/scid mouse. Results: Screening of an inhouse natural compound library identified the AO as a novel inhibitor of GOT1 and repressed glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Virtual docking anal. suggested that AO could bind to the active site of GOT1 and form obvious hydrophobic interaction with Trp141 together with hydrogen bonds with Thr110 and Ser256. Further in vitro validation, including MST, CETSA and DARTS, further demonstrated the specific combining capacity of AO. We also show that the selective inhibition of GOT1 by AO significantly reduces proliferation of PDAC in vitro and in vivo. Conclusions: Taken together, our findings identify AO as a potent bioactive inhibitor of GOT1 and a novel anti-tumor agent for PDAC therapy.
Cell Communication and Signaling published new progress about Antitumor agents. 97-67-6 belongs to class alcohols-buliding-blocks, name is (S)-2-hydroxysuccinic acid, and the molecular formula is C4H6O5, Safety of (S)-2-hydroxysuccinic acid.
Referemce:
Alcohol – Wikipedia,
Alcohols – Chemistry LibreTexts