Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 238, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114446
Keywords
ALKBH5; Epigenetics; RNA modification; N-6-methyladenosine; Structure-activity relationship analysis
Categories
Funding
- National Natural Science Foundation of China [81930125, 82130104]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYXY21001, ZYGD18001]
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This study reports a new class of ALKBH5 inhibitors, which show therapeutic potential for various human diseases, especially cancers. Among them, compound 20m is the most potent one, with high selectivity and cellular activity.
AlkB homolog 5 (ALKBH5) is an RNA m6A demethylase involved in the regulation of genes transcription, translation and metabolism and has been considered as a promising therapeutic target for various human diseases, especially cancers. However, there is still a lack of potent and selective ALKBH5 inhibitors. Herein, we report a new class of ALKBH5 inhibitors containing the 1-aryl-1H-pyrazole scaffold, which were obtained through fluorescence polarization-based screening, structural optimization and structure-activity relationship analysis. Among these compounds, 20m was the most potent one, which showed an IC50 value of 0.021 mu M in fluorescence polarization assay. Compound 20m exhibited high selectivity towards ALKBH5 versus FTO as well as other AlkB subfamily members, indicating good selectivity for ALKBH5. Cellular thermal shift assay (CETSA) analysis showed that 20m could efficiently stabilize ALKBH5 in HepG2 cells. Dot blot assay demonstrated that 20m could increase m6A level in intact cells. Collectively, 20m is a potent, selective and cell active ALKBH5 inhibitor and could be used as a versatile chemical probe to explore the biological function of ALKBH5.
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