期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 23, 页码 17031-17050出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00605
关键词
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资金
- PRIN [20152TE5PK]
- AIRC [24942, 19162]
- Sapienza University Grant [RM11715C7CA6CE53]
- Regione Lazio PROGETTI DI GRUPPI DI RICERCA [2020.A0375-2020-36597]
- Cancer Research UK [A23900, C33483/A25674, C8717/A18245]
- Arthritis Research UK [205222]
- Leducq Foundation
- Wellcome Trust [092809/Z/10/Z, 106244/Z/14/Z]
- AbbVie [1097737]
- Bayer Pharma AG
- Canada Foundation for Innovation
- Boehringer Ingelheim
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Merck Co.
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
New MINA53 inhibitors have been successfully identified, showing selective effects on cancer cells and antiproliferative activity, and enhancing the sensitivity of cancer cells to conventional chemotherapy drugs. These findings provide potential for further exploration of the role of MINA53 inhibitors in combination therapies.
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.
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