Abstract
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.
Highlights
MYC-induced nuclear antigen (MINA53), known as mineral dust-induced gene (Mdig) and ribosomal oxygenase 2 (RIOX2), is a JmjC (Jumonji-C) domain-containing 2oxoglutarate (2OG)-dependent oxygenase localizing to the nucleolus,[1] which is transcriptionally stimulated by the oncoprotein c-MYC.[2]
Our combined results validate the tractability of selective inhibition of the 2OG-dependent ribosomal oxygenases, and in particular, the cancer-linked enzyme MINA53, via targeting their Fe(II) containing catalytic site
Crystallographic analyses with KDM5B suggest an unprecedented mode of 2OG oxygenase inhibition in which C-2-substituted pyrimidine 5carboxylic acids bind adjacent to the Fe(II) but do not directly chelate it; the inhibitors occupy the 2OG binding site and interact with the metal ion via water molecules
Summary
MYC-induced nuclear antigen (MINA53), known as mineral dust-induced gene (Mdig) and ribosomal oxygenase 2 (RIOX2), is a JmjC (Jumonji-C) domain-containing 2oxoglutarate (2OG)-dependent oxygenase localizing to the nucleolus,[1] which is transcriptionally stimulated by the oncoprotein c-MYC.[2]. Elevated MINA53 expression is reported as a poor prognostic indicator, and there is evidence that MINA53 downregulation impairs the proliferation and survival of cancer cells.[3−11] MINA53 expression is induced by silica particles, suggesting a role for MINA53 in allergen-induced inflammation,[12] and, importantly, in the differentiation of proinflammatory TH17 cells.[13] MINA53 is proposed as an important regulator in inflammation and oncology; the underlying molecular mechanisms by which MINA53 is linked to disease are unclear.[11]. MINA53 has been shown to catalyze hydroxylation of a histidine residue in the ribosomal protein RPL27A in studies with both isolated components and in cells, suggesting its function in ribosomal regulation (Figure 1).[15−17] NO66 (nucleolar protein 66), Received: April 1, 2021 Published: November 29, 2021
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