Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells
N<sup>6</sup>A-methyladenosine (m<sup>6</sup>A) post-transcriptional modification, the most abundant internal RNA modification, is catalyzed by the METTL3-14 methyltransferase complex. Recently, attention has been drawn to the METTL3-14 complex regarding its significant roles...
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MDPI AG
2022-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/4/440 |
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| author | Je-Heon Lee Namjeong Choi Subin Kim Mi Sun Jin Haihong Shen Yong-Chul Kim |
| author_facet | Je-Heon Lee Namjeong Choi Subin Kim Mi Sun Jin Haihong Shen Yong-Chul Kim |
| author_sort | Je-Heon Lee |
| collection | DOAJ |
| description | N<sup>6</sup>A-methyladenosine (m<sup>6</sup>A) post-transcriptional modification, the most abundant internal RNA modification, is catalyzed by the METTL3-14 methyltransferase complex. Recently, attention has been drawn to the METTL3-14 complex regarding its significant roles in the pathogenesis of acute myeloid leukemia (AML), attracting the potential of novel therapeutic targets for the disease. Herein, we report the identification and characterization of eltrombopag as a selective allosteric inhibitor of the METTL3-14 complex. Eltrombopag exhibited selective inhibitory activity in the most active catalytic form of the METTL3-14 complex by direct binding, and the mechanism of inhibition was confirmed as a noncompetitive inhibition by interacting at a putative allosteric binding site in METTL3, which was predicted by cavity search and molecular docking studies. At a cellular level, eltrombopag displayed anti-proliferative effects in the relevant AML cell line, MOLM-13, in correlation with a reduction in m<sup>6</sup>A levels. Molecular mechanism studies of eltrombopag using m<sup>6</sup>A-seq analysis provided further evidence of its cellular function by determining the hypomethylation of leukemogenic genes in eltrombopag-treated MOLM-13 cells and the overlapping of the pattern with those of METTL3-knockdown MOLM-13 cells. In conclusion, eltrombopag was first disclosed as a functional METTL3-14 allosteric inhibitor in AML cells, which could be utilized for the further development of novel anti-AML therapy. |
| first_indexed | 2024-03-09T04:19:32Z |
| format | Article |
| id | doaj.art-f3f711aa9779494c807ddc684e874a6b |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T04:19:32Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-f3f711aa9779494c807ddc684e874a6b2023-12-03T13:49:39ZengMDPI AGPharmaceuticals1424-82472022-04-0115444010.3390/ph15040440Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia CellsJe-Heon Lee0Namjeong Choi1Subin Kim2Mi Sun Jin3Haihong Shen4Yong-Chul Kim5School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, KoreaN<sup>6</sup>A-methyladenosine (m<sup>6</sup>A) post-transcriptional modification, the most abundant internal RNA modification, is catalyzed by the METTL3-14 methyltransferase complex. Recently, attention has been drawn to the METTL3-14 complex regarding its significant roles in the pathogenesis of acute myeloid leukemia (AML), attracting the potential of novel therapeutic targets for the disease. Herein, we report the identification and characterization of eltrombopag as a selective allosteric inhibitor of the METTL3-14 complex. Eltrombopag exhibited selective inhibitory activity in the most active catalytic form of the METTL3-14 complex by direct binding, and the mechanism of inhibition was confirmed as a noncompetitive inhibition by interacting at a putative allosteric binding site in METTL3, which was predicted by cavity search and molecular docking studies. At a cellular level, eltrombopag displayed anti-proliferative effects in the relevant AML cell line, MOLM-13, in correlation with a reduction in m<sup>6</sup>A levels. Molecular mechanism studies of eltrombopag using m<sup>6</sup>A-seq analysis provided further evidence of its cellular function by determining the hypomethylation of leukemogenic genes in eltrombopag-treated MOLM-13 cells and the overlapping of the pattern with those of METTL3-knockdown MOLM-13 cells. In conclusion, eltrombopag was first disclosed as a functional METTL3-14 allosteric inhibitor in AML cells, which could be utilized for the further development of novel anti-AML therapy.https://www.mdpi.com/1424-8247/15/4/440eltrombopagMETTL3-14allosteric inhibitoracute myeloid leukemia |
| spellingShingle | Je-Heon Lee Namjeong Choi Subin Kim Mi Sun Jin Haihong Shen Yong-Chul Kim Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells Pharmaceuticals eltrombopag METTL3-14 allosteric inhibitor acute myeloid leukemia |
| title | Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells |
| title_full | Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells |
| title_fullStr | Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells |
| title_full_unstemmed | Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells |
| title_short | Eltrombopag as an Allosteric Inhibitor of the METTL3-14 Complex Affecting the m<sup>6</sup>A Methylation of RNA in Acute Myeloid Leukemia Cells |
| title_sort | eltrombopag as an allosteric inhibitor of the mettl3 14 complex affecting the m sup 6 sup a methylation of rna in acute myeloid leukemia cells |
| topic | eltrombopag METTL3-14 allosteric inhibitor acute myeloid leukemia |
| url | https://www.mdpi.com/1424-8247/15/4/440 |
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