A covalent small molecule inhibitor of glutamate-oxaloacetate transaminase 1 impairs pancreatic cancer growth.
A covalent small molecule inhibitor of glutamate-oxaloacetate transaminase 1 impairs pancreatic cancer growth.
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DOI：
10.1016/j.bbrc.2019.11.130
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发表时间：
2019-11
影响因子：
3.1
通讯作者：
Tomohiro Yoshida;S. Yamasaki;O. Kaneko;Naofumi Taoka;Y. Tomimoto;I. Namatame;Toshiko Yahata;
中科院分区：
文献类型：
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作者：
Tomohiro Yoshida;S. Yamasaki;O. Kaneko;Naofumi Taoka;Y. Tomimoto;I. Namatame;Toshiko Yahata;
癌细胞中的代谢程序被重新连接以支持生存和肿瘤生长。其中，最近的研究表明，谷氨酸-草酰乙酸转氨酶1（GOT1）在维持氧化还原稳态和胰腺导管腺癌（PDA）的增殖中发挥着关键作用。这表明 GOT1 的小分子抑制剂可用于治疗 PDA。然而，GOT1抑制剂的开发一直具有挑战性，目前还没有化合物表现出对GOT1依赖性细胞代谢的选择性或对PDA细胞系的选择性生长抑制。相比之下，已报道犬尿氨酸转氨酶 (KAT) 和 γ-氨基丁酸转氨酶 (GABA-AT) 的有效抑制剂在酶的活性位点内与转氨酶辅因子吡哆醛-5'-磷酸 (PLP) 共价结合。鉴于这些转氨酶药物发现的成功，我们的目标是鉴定 PLP 依赖性自杀底物型 GOT1 抑制剂。在这里，我们证明了 PF-04859989（一种已知的 KAT2 抑制剂）对 GOT1 具有 PLP 依赖性抑制活性，并显示出对 PDA 细胞系的选择性生长抑制。
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.