Discovery of novel METTL3 inhibitors: design, synthesis, and in silico and in vitro evaluations.

Methyltransferase-like protein 3 (METTL3) is a promising therapeutic target for Acute Myeloid Leukemia (AML). To discover novel METTL3 inhibitors, we designed a series of compounds by hybridizing the natural product Genistein and the non-nucleoside METTL3 inhibitor STM2457. Among the 31 de novo-generated compounds subjected to molecular docking, the top-scoring hit H1 was selected for chemical synthesis and its structure was confirmed by NMR and MS. H1 showed an inhibitory activity against METTL3 with an IC50 value of 980.3 nM, significantly better than Genistein (37.31% inhibition at 40 µM). Molecular docking revealed that H1's binding mode was similar to STM2457, forming hydrogen bonds and hydrophobic interactions within the METTL3 pocket. Druglikeness prediction by SwissADMET and ADMETlab 3.0 showed that H1 exhibited to be within an acceptable range. This study validated our design strategy and provided a foundation for developing more potent and selective METTL3 inhibitors.