First-in-class inhibitors of the ribosomal oxygenase MINA53

Journal article

MINA53 is a JmjC domain 2-oxoglutarate dependent oxygenase that catalyzes ribosomal hydroxylation and which 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 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 indicate 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 further work investigating their potential in combination therapies is warranted.

Authors: Nowak, R; Tumber, A; Hendrix, E; Ansari, M; Sabatino, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry
• Volume: 64
• Issue: 23
• Pages: 17031–17050
• Publication date: 2021-11-29
• Acceptance date: 2021-11-18
• DOI: 10.1021/acs.jmedchem.1c00605
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Keywords: FFR