Targeting METTL3 protein by proteolysis-targeting chimeras: A novel therapeutic approach for acute myeloid leukemia

Despite numerous studies suggesting that RNA m⁶A transferase core complex including METTL3 and METTL14 play essential roles in both the initiation and maintenance of acute myeloid leukemia (AML), effective pharmacological targeting of these two proteins remains elusive. Here, we report the development and evaluation of a novel METTL3 degrader, ZW27941, designed to induce METTL3 degradation via the VHL-mediated proteasomal degradation pathway. ZW27941 exhibited potent and selective degradation of METTL3 and its binding partner METTL14, leading to significant anti-leukemic activity in AML cell lines. Furthermore, ZW27941 demonstrated synergistic or additive effects when combined with standard AML therapeutics, such as cytarabine and venetoclax. Our findings suggest that selective METTL3 degraders, exemplified by ZW27941, hold promise as a novel therapeutic approach for AML, particularly when used in combination with existing treatments to enhance efficacy and overcome resistance mechanisms.