First-in-Class Inhibitors of the Ribosomal Oxygenase MINA53

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• MINA53 is a JmjC oxygenase involved in ribosomal hydroxylation and targeted by c-MYC.
• No small-molecule inhibitors for MINA53 have been previously reported.
• MINA53 presents a potential target for anticancer drug development.

Purpose of the Study:

• To develop and identify small-molecule inhibitors of MINA53.
• To assess the selectivity and mechanism of action of identified inhibitors.
• To evaluate the therapeutic potential of MINA53 inhibitors in cancer treatment.

Main Methods:

• Development of mass spectrometry assays for MINA53 and NO66 using ribosomal substrate fragments.
• High-throughput screening to identify MINA53 inhibitors.
• Crystallography and molecular modeling to elucidate inhibitor binding modes.
• In vitro assays to assess target engagement, selectivity, and antiproliferative activity.

Main Results:

• Identification of 2-(aryl)alkylthio-3,4-dihydro-4-oxopyrimidine-5-carboxylic acids as potent MINA53 inhibitors.
• Demonstrated selectivity of inhibitors for MINA53 over NO66 and other JmjC oxygenases (KDM4-6).
• Inhibitors bind to MINA53 via interaction with the iron cofactor and exhibit antiproliferative effects on solid cancer lines.
• MINA53 inhibitors sensitize cancer cells to conventional chemotherapy.

Conclusions:

• Novel MINA53 inhibitors have been discovered with demonstrated target engagement and selectivity.
• These inhibitors exhibit anticancer activity and enhance chemotherapy efficacy.
• Further investigation into MINA53 inhibitors for combination cancer therapies is warranted.