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. 2024 Dec 5:279:116843.
doi: 10.1016/j.ejmech.2024.116843. Epub 2024 Sep 6.

Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer

Kyubin Hwang  1 , Juhyeon Bae  1 , Yoo-Lim Jhe  2 , Jungmin Kim  2 , Jae-Ho Cheong  3 , Ha-Soon Choi  4 , Taebo Sim  5
Affiliations

Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer

Kyubin Hwang et al. Eur J Med Chem. .

Abstract

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m6A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes degradation of METTL3 with a DC50 value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 is capable of reversing differentiation and possesses anti-proliferative effects surpassing the small molecule inhibitors on MOLM-13 cells. Notably, we first present that METTL3 degrader significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of KH12 were further confirmed in patient-derived organoids (PDOs). This study offers therapeutic potentials of targeted degradation of METTL3 against GC implicated with non-catalytic function of METTL3 as well as against AML.

Keywords: Acute myeloid leukemia; Gastric cancer; METTL3; Methyltransferase; PROTAC; Targeted protein degradation.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Taebo Sim reports financial support was provided by National Research Foundation of Korea. Jae-Ho Cheong reports financial support was provided by National Research Foundation of Korea. Taebo Sim reports a relationship with Magicbullettherapeutics Inc. that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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