A covalent small molecule inhibitor of glutamate-oxaloacetate transaminase 1 impairs pancreatic cancer growth

• Published in: Biochemical and biophysical research communications Vol. 522; no. 3; pp. 633 - 638
• Main Authors: Yoshida, Tomohiro, Yamasaki, Shingo, Kaneko, Osamu, Taoka, Naofumi, Tomimoto, Yusuke, Namatame, Ichiji, Yahata, Toshiko, Kuromitsu, Sadao, Cantley, Lewis C., Lyssiotis, Costas A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2020
• Subjects: Aminotransferase; Aspartate Aminotransferase, Cytoplasmic - antagonists & inhibitors; Aspartate Aminotransferase, Cytoplasmic - metabolism; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - enzymology; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Discovery; Enzyme Inhibitors - pharmacology; GOT1; Humans; Metabolism; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; PLP; Pyrazoles - pharmacology; Transaminase; GOT1; Metabolism; PLP; Transaminase; Pancreatic cancer; Aminotransferase
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.11.130

Metabolic programs are rewired in cancer cells to support survival and tumor growth. Among these, recent studies have demonstrated that glutamate-oxaloacetate transaminase 1 (GOT1) plays key roles in maintaining redox homeostasis and proliferation of pancreatic ductal adenocarcinomas (PDA). This suggests that small molecule inhibitors of GOT1 could have utility for the treatment of PDA. However, the development of GOT1 inhibitors has been challenging, and no compound has yet demonstrated selectivity for GOT1-dependent cell metabolism or selective growth inhibition of PDA cell lines. In contrast, potent inhibitors that covalently bind to the transaminase cofactor pyridoxal-5′-phosphate (PLP), within the active site of the enzyme, have been reported for kynurenine aminotransferase (KAT) and gamma-aminobutyric acid aminotransferase (GABA-AT). Given the drug discovery successes with these transaminases, we aimed to identify PLP-dependent suicide substrate-type GOT1 inhibitors. Here, we demonstrate that PF-04859989, a known KAT2 inhibitor, has PLP-dependent inhibitory activity against GOT1 and shows selective growth inhibition of PDA cell lines. •A suicide inhibitor of glutamate-oxaloacetate transaminase 1 (GOT1) is identified.•The GOT1 inhibitor acts by covalently modifying the pyridoxal phosphate co-factor.•Pancreatic cancer cells are selectively sensitive to the GOT1 inhibitor.•Proliferative defects of the GOT1 inhibitor are reversed by the GOT1 reaction product.