Glutamate-oxaloacetate transaminase (GOT) is a Pyr aldehyde phosphate-dependent enzyme. Specifically, it exists in the form of cytoplasm and mitochondria, GOT1, and GOT2, respectively. Besides, GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycle. Besides, pancreatic cancer cells are characterized by metabolic disorders that promote growth and resist oxidative stress. Pancreatic ductal adenocarcinoma (PDAC) depends on the metabolic pathway involving GOT1 to maintain redox homeostasis and sustained proliferation. Furthermore, some PDACs depend on the nonstandard Gln metabolic pathway regulated by KRAS, thus promoting proliferation and tumor growth. Thus, small molecule inhibitors targeting this metabolic pathway can provide novel therapeutic methods for this destructive disease. Meanwhile, GOT1 knockdown in PDAC inhibited the growth in vitro and in vivo, while GOT1 knockdown in normal cells had no effect on proliferation. iGOT1-01 is a potent aspartate aminotransferase 1 (glutamate oxaloacetate transaminase 1; GOT1) inhibitor.
iGOT1-01 is a potent aspartate aminotransferase 1 (GOT1) inhibitor.
But, how does iGOT1-01 work on the target? Let’s discuss it in detail. In the beginning, iGOT1-01 is a potent GOT1 inhibitor with anti-cancer activity. Nonetheless, iGOT1-01 has IC50s of 85 μM and 11.3 μM in MDH coupled GOT1 enzymatic assay and GOT1/GLOX/HRP assay, respectively.
In the second place, iGOT1-01 has an IC50 of 84.6 μM in the GOT1/MDH1 assay. Nonetheless, no inhibitory activity is observed for iGOT1-01 against MDH1 alone at 100 μM. Nonetheless, iGOT1-01 reveals little to no toxicity using two readouts of cell viability in PaTu8902 pancreatic and DLD1 colon cancer cells.
Last but not the least, iGOT1-01 has reasonable bioavailability and exposure properties (t1/2=0.7 hours, Cmax=4133 ng/mL, AUC(0-24 hours)=11734 hour•ng/mL).
All in all, iGOT1-01 is a potent GOT1 inhibitor with anti-cancer activity.
References:
Justin Anglin, et al. Bioorg Med Chem Lett. 2018 Sep 1;28(16):2675-2678.