MINA53 is a JmjC domain 2-oxoglutarate-dependent oxygenase that catalyzes ribosomal hydroxylation and is a target of the oncogenic transcription factor c-MYC. Despite its anticancer target potential, no small-molecule MINA53 inhibitors are reported. Using ribosomal substrate fragments, we developed mass spectrometry assays for MINA53 and the related oxygenase NO66. These assays enabled the identification of 2-(aryl)alkylthio-3,4-dihydro-4-oxoypyrimidine-5-carboxylic acids as potent MINA53 inhibitors, with selectivity over NO66 and other JmjC oxygenases. Crystallographic studies with the JmjC demethylase KDM5B revealed active site binding but without direct metal chelation; however, molecular modeling investigations indicated that the inhibitors bind to MINA53 by directly interacting with the iron cofactor. The MINA53 inhibitors manifest evidence for target engagement and selectivity for MINA53 over KDM4–6. The MINA53 inhibitors show antiproliferative activity with solid cancer lines and sensitize cancer cells to conventional chemotherapy, suggesting that further work investigating their potential in combination therapies is warranted.

中文翻译：

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一流的核糖体加氧酶抑制剂 MINA53

MINA53 是一种 JmjC 结构域 2-酮戊二酸依赖性加氧酶，可催化核糖体羟基化，是致癌转录因子c的靶标-我的C。尽管具有抗癌靶标潜力，但尚未报道小分子 MINA53 抑制剂。使用核糖体底物片段，我们开发了 MINA53 和相关加氧酶 NO66 的质谱分析。这些测定能够将 2-(aryl)alkylthio-3,4-dihydro-4-oxoypyrimidine-5-carboxylic acids 鉴定为有效的 MINA53 抑制剂，选择性高于 NO66 和其他 JmjC 加氧酶。使用 JmjC 去甲基化酶 KDM5B 的晶体学研究揭示了活性位点结合但没有直接金属螯合；然而，分子模型研究表明，抑制剂通过直接与铁辅助因子相互作用而与 MINA53 结合。MINA53 抑制剂表明 MINA53 的目标参与和选择性优于 KDM4-6。