Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m 6 A 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 DC 50 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 m 6 A-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.
Keyphrases
- induced apoptosis
- acute myeloid leukemia
- small molecule
- cell cycle arrest
- cancer therapy
- signaling pathway
- endoplasmic reticulum stress
- oxidative stress
- cell death
- transcription factor
- drug delivery
- photodynamic therapy
- gas chromatography
- acute lymphoblastic leukemia
- replacement therapy
- anti inflammatory
- smoking cessation