METTL1 x METTL16 x METTL18 x METTL3 x METTL6

The development of more efficient and durable multi-targeted therapeutic drug against hepatocellular carcinoma (HCC) has recently been of growing interest to tackle chemoresistance. Several studies indicate that increased expression of methyltransferase-like (METTL) proteins, including METTL1, METTL3, METTL6, METTL16, and METTL18, are associated with the progression of HCC malignancy, making them potential biomarkers. Here, using a series of computer-aided drug design (CADD) approaches, we identified two first-in-class highly potent catalytic multi-target inhibitors (ZINC70666503 and ZINC13000658 with 87% and 82% predicted drug scores, respectively) of these five methyltransferase-like proteins. The molecular dynamics study supported their conformational stability with these METTL proteins and high selectivity at the pocket of proteins' adenosine moiety of S-Adenosyl Methionine. Further in vitro experiments revealed significant anti-proliferative activity and effects on the cell cycle of ZINC13000658 against two HCC cell lines, HepG2 and SNU-449. This work provides evidence that multitargeted METTL may have stronger inhibition of HCC cell proliferation. Further in vivo validation, toxicity analysis as well as molecular insights will determine the therapeutic utility against HCC.