Research progress of N<sup>6</sup>-methyladenine demethylase inhibitors

GAO Jing; MI Xue; ZHOU Qi; ZHOU Jun

doi:10.11665/j.issn.1000-5048.20220604

Journal of China Pharmaceutical University > 2022 > 53(6): 663-673. > DOI: 10.11665/j.issn.1000-5048.20220604

GAO Jing, MI Xue, ZHOU Qi, ZHOU Jun. Research progress of N⁶-methyladenine demethylase inhibitors[J]. Journal of China Pharmaceutical University, 2022, 53(6): 663-673. DOI: 10.11665/j.issn.1000-5048.20220604

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Research progress of N⁶-methyladenine demethylase inhibitors

School of Life Science & Technology, China Pharmaceutical University, Nanjing 211198, China

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Received Date: September 04, 2022
Revised Date: November 06, 2022

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Abstract

Abstract

N⁶-methyladenine (m⁶A) modification, the most abundant and dynamic chemical modification on messenger RNA, plays an essential role in physiological and pathological progress.Recent studies have found that tumor progression can be affected by altering the m⁶A modification level of target genes. Therefore, small molecule targeted m⁶A demethylase can be used as a new anti-tumor strategy.This review focuses on the regulatory mechanism of m⁶A demethylases, including fat mass and obesity-associated protein (FTO) and AlkB homlog 5 (ALKBH5), as well as their biological functions in tumors, and summarizes the research progress of their small molecule inhibitors.
- N⁶-methyladenosine (m⁶A),
- demethylase,
- fat mass and obesity-associated protein,
- AlkB homlog 5,
- enzyme inhibitors,
- progress

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References (61)

References

[1]	. Nucleic Acids Res，2021，50（D1）：D231-D235.
[2]	Desrosiers R，Friderici K，Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells［J］. Proc Natl Acad Sci U S A，1974，71（10）：3971-3975.
[3]	Yang Y，Hsu PJ，Chen YS，et al. Dynamic transcriptomic m⁶A decoration：writers，erasers，readers and functions in RNA metabolism［J］. Cell Res，2018，28（6）：616-624.
[4]	Li ZJ，Weng HY，Su R，et al. FTO plays an oncogenic role in acute myeloid leukemia as a N⁶-methyladenosine RNA demethylase［J］. Cancer Cell，2017，31（1）：127-141.
[5]	Li J，Han Y，Zhang HM，et al. The m⁶A demethylase FTO promotes the growth of lung cancer cells by regulating the m⁶A level of USP7 mRNA［J］. Biochem Biophys Res Commun，2019，512（3）：479-485.
[6]	Ding YD，Qi NN，Wang K，et al. FTO facilitates lung adenocarcinoma cell progression by activating cell migration through mRNA demethylation［J］. Onco Targets Ther，2020，13：1461-1470.
[7]	Zhang SC，Zhao BS，Zhou AD，et al. m⁶A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program［J］. Cancer Cell，2017，31（4）：591-606.e6.
[8]	Hu YY，Gong CL，Li ZB，et al. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m⁶A modification［J］. Mol Cancer，2022，21（1）：34.
[9]	Jia GF，Fu Y，Zhao X，et al. N⁶-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO［J］. Nat Chem Biol，2011，7（12）：885-887.
[10]	Dominissini D，Moshitch-Moshkovitz S，Schwartz S，et al. Topo-logy of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq［J］. Nature，2012，485（7397）：201-206.
[11]	Meyer KD，Saletore Y，Zumbo P，et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons［J］. Cell，2012，149（7）：1635-1646.
[12]	Schwartz S，Agarwala SD，Mumbach MR，et al. High-resolution mapping reveals a conserved，widespread，dynamic mRNA methylation program in yeast meiosis［J］. Cell，2013，155（6）：1409-1421.
[13]	Selberg S，?usinaite E，Herodes K，et al. HIV replication is increased by RNA methylation METTL3/METTL14/WTAP complex activators［J］. ACS Omega，2021，6（24）：15957-15963.
[14]	Li ZX，Zheng ZQ，Yang PY，et al. WTAP-mediated m⁶A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis［J］. Cell Death Differ，2022，29（6）：1137-1151.
[15]	Yue YN，Liu J，Cui XL，et al. VIRMA mediates preferential m⁶A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation［J］. Cell Discov，2018，4：10.
[16]	Patil DP，Chen CK，Pickering BF，et al. m⁶A RNA methylation promotes XIST-mediated transcriptional repression［J］. Nature，2016，537（7620）：369-373.
[17]	Bawankar P，Lence T，Paolantoni C，et al. Hakai is required for stabilization of core components of the m⁶A mRNA methylation machinery［J］. Nat Commun，2021，12（1）：3778.
[18]	Wen J，Lv RT，Ma HH，et al. Zc3h13 regulates nuclear RNA m⁶A methylation and mouse embryonic stem cell self-renewal［J］. Mol Cell，2018，69（6）：1028-1038.e6.
[19]	Su R，Dong L，Li YC，et al. METTL16 exerts an m⁶A-independent function to facilitate translation and tumorigenesis［J］. Nat Cell Biol，2022，24（2）：205-216.
[20]	Zhang Z，Wang L，Zhao L，et al. N⁶-methyladenosine demethy-lase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation［J］. Clin Transl Med，2022，12（8）：e940.
[21]	Li Q，Ni Y，Zhang LR，et al. HIF-1α-induced expression of m⁶A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation［J］. Signal Transduct Target Ther，2021，6（1）：76.
[22]	Heck AM，Russo J，Wilusz J，et al. YTHDF2 destabilizes m⁶A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells［J］. RNA，2020，26（6）：739-755.
[23]	Shi HL，Wang X，Lu ZK，et al. YTHDF3 facilitates translation and decay of N⁶-methyladenosine-modified RNA［J］. Cell Res，2017，27（3）：315-328.
[24]	Jiang FJ，Tang XZ，Tang C，et al. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m⁶A-dependent stabilization of ILF3 mRNA［J］. J Hematol Oncol，2021，14（1）：54.
[25]	Huang H，Weng H，Sun W，et al. Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation［J］.Nat Cell Biol， 2018，20（9）：1098. doi：10.1038/s41556-018-0045-z.
[26]	Roundtree IA，Luo GZ，Zhang ZJ，et al. YTHDC1 mediates nuclear export of N⁶-methyladenosine methylated mRNAs［J］. eLife，2017，6：e31311.
[27]	Huang XT，Li JH，Zhu XX，et al. HNRNPC impedes m⁶A-dependent anti-metastatic alternative splicing events in pancreatic ductal adenocarcinoma［J］. Cancer Lett，2021，518：196-206.
[28]	Wu R，Li A，Sun BF，et al. A novel m⁶A reader Prrc2a controls oligodendroglial specification and myelination［J］. Cell Res，2019，29（1）：23-41.
[29]	Condic M，Ralser DJ，Klümper N，et al. Comprehensive analysis of N⁶-methyladenosine （m⁶A） writers，erasers，and readers in cervical cancer［J］. Int J Mol Sci，2022，23（13）：7165.
[30]	Gerken T，Girard CA，Tung YCL，et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase［J］. Science，2007，318（5855）：1469-1472.
[31]	Jia GF，Yang CG，Yang SD，et al. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO［J］. FEBS Lett，2008，582（23/24）：3313-3319.
[32]	Zhao X，Yang Y，Sun BF，et al. FTO-dependent demethylation of N⁶-methyladenosine regulates mRNA splicing and is required for adipogenesis［J］. Cell Res，2014，24（12）：1403-1419.
[33]	Niu Y，Lin ZY，Wan A，et al. RNA N⁶-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3［J］. Mol Cancer，2019，18（1）：46.
[34]	Tao L，Mu X，Chen H，et al. FTO modifies the m⁶A level of MALAT and promotes bladder cancer progression［J］. Clin Transl Med，2021，11（2）：e310.
[35]	Yang S，Wei JB，Cui YH，et al. m⁶A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade［J］. Nat Commun，2019，10（1）：2782.
[36]	Zhou S，Bai ZL，Xia D，et al. FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma （CSCC） by targeting β-catenin through mRNA demethylation［J］. Mol Carcinog，2018，57（5）：590-597.
[37]	Zheng GQ，Dahl JA，Niu YM，et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility［J］. Mol Cell，2013，49（1）：18-29.
[38]	Tang C，Klukovich R，Peng HY，et al. ALKBH5-dependent m⁶A demethylation controls splicing and stability of long 3'-UTR mRNAs in male germ cells［J］. Proc Natl Acad Sci U S A，2018，115（2）：E325-E333.
[39]	Song HW，Feng X，Zhang H，et al. METTL3 and ALKBH5 oppositely regulate m⁶A modification of TFEB mRNA，which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes［J］. Autophagy，2019，15（8）：1419-1437.
[40]	Zhang J，Guo S，Piao HY，et al. ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1［J］. J Physiol Biochem，2019，75（3）：379-389.
[41]	Chao YH，Shang J，Ji WD. ALKBH5-m⁶A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia［J］. Biochem Biophys Res Commun，2020，521（2）：499-506.
[42]	Zhu HT，Gan XL，Jiang XW，et al. ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2［J］. J Exp Clin Cancer Res，2019，38（1）：163.
[43]	Li N，Kang YQ，Wang LL，et al. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment［J］. Proc Natl Acad Sci U S A，2020，117（33）：20159-20170.
[44]	Aik W，Demetriades M，Hamdan MKK，et al. Structural basis for inhibition of the fat mass and obesity associated protein （FTO）［J］. J Med Chem，2013，56（9）：3680-3688.
[45]	Chen BE，Ye F，Yu L，et al. Development of cell-active N⁶-methyladenosine RNA demethylase FTO inhibitor［J］. J Am Chem Soc，2012，134（43）：17963-17971.
[46]	Li Q，Huang Y，Liu XC，et al. Rhein inhibits AlkB repair enzymes and sensitizes cells to methylated DNA damage［J］. J Biol Chem，2016，291（21）：11083-11093.
[47]	Huang Y，Yan JL，Li Q，et al. Meclofenamic acid selectively inhibits FTO demethylation of m⁶A over ALKBH5［J］. Nucleic Acids Res，2014，43（1）：373-384.
[48]	Toh JDW，Sun LY，Lau LZM，et al. A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO［J］. Chem Sci，2015，6（1）：112-122.
[49]	He W，Zhou B，Liu WJ，et al. Identification of A novel small-molecule binding site of the fat mass and obesity associated protein （FTO）［J］. J Med Chem，2015，58（18）：7341-7348.
[50]	Qiao Y，Zhou B，Zhang M，et al. A novel inhibitor of the obesity-related protein FTO［J］. Biochemistry，2016，55（10）：1516-1522.
[51]	Wang RY，Han ZF，Liu BJ，et al. Identification of natural compound radicicol as a potent FTO inhibitor［J］. Mol Pharm，2018，15（9）：4092-4098.
[52]	Huang Y，Su R，Sheng Y，et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia［J］. Cancer Cell，2019，35（4）：677-691.e10.
[53]	Peng SM，Xiao W，Ju DP，et al. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1［J］. Sci Transl Med，2019，11（488）：eaau7116.
[54]	Su R，Dong L，Li YC，et al. Targeting FTO suppresses cancer stem cell maintenance and immune evasion［J］. Cancer Cell，2020，38（1）：79-96.e11.
[55]	Cao KX，Du YY，Bao X，et al. Glutathione-bioimprinted nanoparticles targeting of N⁶-methyladenosine FTO demethylase as a strategy against leukemic stem cells［J］. Small，2022，18（13）：e2106558.
[56]	Xie G，Wu XN，Ling Y，et al. A novel inhibitor of N⁶-methy-ladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities［J］. Acta Pharm Sin B，2022，12（2）：853-866.
[57]	Xu C，Liu K，Tempel W，et al. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N⁶-methyladenosine RNA demethylation［J］. J Biol Chem，2014，289（25）：17299-17311.
[58]	Malacrida A，Rivara M，Di Domizio A，et al. 3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line［J］. Bioorg Med Chem，2020，28（4）：115300.
[59]	Fang Z，Mu B，Liu Y，et al. Discovery of a potent，selective and cell active inhibitor of m⁶A demethylase ALKBH5［J］. Eur J Med Chem，2022，238（（19））：114446.
[60]	Tan Z，Shi S，Xu J，et al. RNA N⁶-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m⁶A-YTHDF2-dependent manner［J］. Oncogene，2022，41（20）：2860-2872.
[61]	Cui Q，Shi HL，Ye P，et al. m⁶A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells［J］. Cell Rep，2017，18（11）：2622-2634.

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Research progress of N6-methyladenine demethylase inhibitors

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Research progress of N⁶-methyladenine demethylase inhibitors