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bioRxiv · 10.1101/2024.02.02.578521

Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer.

Hwang, K.·Bae, J.·Jhe, Y.-L.·Kim, J.·Cheong, J.-H.·Sim, T.
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Abstract

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancer types, either dependent or independent of its m6A methyl transferase activity. We have designed proteolysis-targeting chimeras (PROTACs) targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes more than 80% degradation of METTL3 with a half-maximal degradation concentration (DC50) of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 reverses differentiation and possesses anti-proliferative effects surpassing the reported inhibitors in MOLM-13 cells. Furthermore, KH12 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 effect of KH12 was further confirmed in patient-derived organoids (PDOs). This study highlights the therapeutic potential of targeted degradation of epitranscriptomic writer METTL3 as an anti-cancer strategy.

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Hwang, K., Bae, J., Jhe, Y.-L., Kim, J., Cheong, J.-H., Sim, T.. 2024-02-03. Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer.. https://doi.org/10.1101/2024.02.02.578521

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