First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53

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.