Research progress of RNA m6A methylation modification in regulating tumor function and its inhibitors

doi:10.3969/j.issn.1674-8115.2021.06.018

Abstract

Abstract:

RNA modifications play an important role in physiology and pathology. N⁶-methyladenine (m⁶A) has been identified as a prevalent methylation modification on eukaryotic RNAs. RNA m⁶A can be reversible. In recent years, abnormal expression of the RNA m⁶A modification enzymes and binding proteins have been found in tumors, and they promote or inhibit the tumor progression by altering the mRNA m⁶A modification levels of the target genes. This paper reviews the important functions of FTO α-ketoglutarate dependent dioxygenase, AlkB homolog 5 (ALKBH5) and methyltransferase like 3 (METTL3) in a variety of tumors, and also reports their small molecule inhibitors.

Key words: RNA N⁶-methyladenine (m⁶A), tumor, inhibitor, FTO α-ketoglutarate dependent dioxygenase

CLC Number:

Q522

Ya-juan HAO, Ying-bin LIU. Research progress of RNA m⁶A methylation modification in regulating tumor function and its inhibitors[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(6): 809-814.

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References 40

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Inhibitor	Mode of action	Reference
MA	MA selectively inhibits FTO demethylation of m⁶A over ALKBH5. MA is a non-steroidal anti-inflammatory drug and mechanistic studies indicate it competes with FTO binding to the m⁶A-containing nucleic acid	[20]
Entacapone	Entacapone directly binds to FTO and inhibites FTO activity in vitro. Entacapone administration reduces body weight and lowers fasting blood glucose concentrations in diet-induced obese mice. FOXO1 mRNA acts as a direct substrate of FTO, and entacapone elicits its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis	[21]
FB23 and FB23-2	FB23 and FB23-2 directly bind to FTO and selectively inhibit FTO's m⁶A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human AML cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice	[22]
Rhein	Rhein is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binding to the FTO-active site in vitro. Rhein also exhibits good inhibitory activity on m⁶A demethylation inside cells	[23-24]
4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol（CHTB）	CHTB is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner	[25]
N-phenyl-1H-indol-2-amine derivatives	N-phenyl-1H-indol-2-amine derivative MU06 shows stable interaction with Arg96 and His231 residue of FTO protein throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) are found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking	[26]
Radicicol	Radicicol is a potent FTO inhibitor, and exhibits a dose-dependent inhibition of FTO demethylation activity with an IC₅₀ value of 16.04 μmol/L. Further ITC experiments show that the binding between radicicol and FTO is mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site	[27]
Nafamostat mesilate	Nafamostat mesilate is a serine protease inhibitor and used for the treatment of pancreatitis and cancers. The binding of nafamostat mesilate to FTO is driven by higher positive entropy changes and smaller negative enthalpy changes	[28]
Clausine E	The binding of Clausine E to FTO is driven by positive entropy and negative enthalpy changes. Results also indicate that the hydroxyl group is crucial for the binding of small molecules with FTO	[29]
2‐phenyl‐1H‐benzimidazole analogues	The binding between 2-phenyl-1H-benzimidazole structural analogue 6-chloro-2-phenyl-1H-benzimidazole (1 d) and FTO is dominated by entropy. Results of enzymatic activity assays provide an IC₅₀ value of 24.65 μmol/L for 1 d. The chlorine atom is crucial for the binding of small molecules with FTO	[30]

Inhibitor	Mode of action	Reference
MA	MA selectively inhibits FTO demethylation of m⁶A over ALKBH5. MA is a non-steroidal anti-inflammatory drug and mechanistic studies indicate it competes with FTO binding to the m⁶A-containing nucleic acid	[20]
Entacapone	Entacapone directly binds to FTO and inhibites FTO activity in vitro. Entacapone administration reduces body weight and lowers fasting blood glucose concentrations in diet-induced obese mice. FOXO1 mRNA acts as a direct substrate of FTO, and entacapone elicits its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis	[21]
FB23 and FB23-2	FB23 and FB23-2 directly bind to FTO and selectively inhibit FTO's m⁶A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human AML cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice	[22]
Rhein	Rhein is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binding to the FTO-active site in vitro. Rhein also exhibits good inhibitory activity on m⁶A demethylation inside cells	[23-24]
4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol（CHTB）	CHTB is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner	[25]
N-phenyl-1H-indol-2-amine derivatives	N-phenyl-1H-indol-2-amine derivative MU06 shows stable interaction with Arg96 and His231 residue of FTO protein throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) are found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking	[26]
Radicicol	Radicicol is a potent FTO inhibitor, and exhibits a dose-dependent inhibition of FTO demethylation activity with an IC₅₀ value of 16.04 μmol/L. Further ITC experiments show that the binding between radicicol and FTO is mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site	[27]
Nafamostat mesilate	Nafamostat mesilate is a serine protease inhibitor and used for the treatment of pancreatitis and cancers. The binding of nafamostat mesilate to FTO is driven by higher positive entropy changes and smaller negative enthalpy changes	[28]
Clausine E	The binding of Clausine E to FTO is driven by positive entropy and negative enthalpy changes. Results also indicate that the hydroxyl group is crucial for the binding of small molecules with FTO	[29]
2‐phenyl‐1H‐benzimidazole analogues	The binding between 2-phenyl-1H-benzimidazole structural analogue 6-chloro-2-phenyl-1H-benzimidazole (1 d) and FTO is dominated by entropy. Results of enzymatic activity assays provide an IC₅₀ value of 24.65 μmol/L for 1 d. The chlorine atom is crucial for the binding of small molecules with FTO	[30]

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Research progress of RNA m⁶A methylation modification in regulating tumor function and its inhibitors

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