Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5

By Yue Huang, Jingli Yan, Qi Li, Jiafei Li, Shouzhe Gong, Hu Zhou, J. Gan, Hualiang Jiang, G. Jia, Cheng Luo and 1 more. Nucleic Acids Research, 2014

614 citations recorded by the source corpus.

Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/97d7d315ee543c108830925fb3286e5f737680f2

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In Cancer Research

1. Chuan He
2. Hailing Shi

In Molecular Biology

1. Chuan He
2. Hailing Shi
3. Jiangbo W
4. Jianjun Chen
5. R. Su
6. Zhike Lu
7. Samie R. Jaffrey
8. P. He

Citations in the corpus

• Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, neutral): “A set of specific or non-specific FTO inhibitors, such as rhein, meclofenamic acid (MA), MO-I-500, fluorescein, and R-2HG, have been identified (Chen et al., 2012; He et al., 2015; Huang et al., 2015; Padariya and Kalathiya, 2016; Singh et al., 2016; Su et al., 2018; Toh et al., 2015; Wang et al., 2”
• m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells (2017, methodology): “…of modifying m6A levels in GSC tumorigenesis in a more clinically relevant system, we transplanted luciferase-reporter-bearing PBT003 cells into brains of NSG mice to establish tumors and treated the mice with an FTO inhibitor that has been shown to modulate mRNA m6A levels (Huang et al., 2015).”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “As the ethyl ester derivative of MA, MA2 suppresses GSC growth and self-renewal in vitro and inhibits tumor growth in vivo [158, 159].”
• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, methodology): “Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5.”