Discovery of maleimide derivatives as m6A demethylase ALKBH5 inhibitors.

Human AlkB homologue H5 (ALKBH5) is a crucial demethylase for N6-methyladenosine (m6A) of mRNA. Although ALKBH5 is recognized as a promising target in various cancers, especially acute myeloid leukemia (AML), research on inhibitors of ALKBH5 remains limited. Here, we reported the discovery of a series of maleimide-based small molecule inhibitors of ALKBH5, resulting in the identification of compound 18 through optimization. Comprehensive evaluations suggested that compound 18 holds significant potential as a lead compound for ALKBH5 inhibitor.