A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO.

ABSTRACT: N ⁶-Methyladenosine (m⁶A) is the most prevalent mRNA modification and is required for gene regulation in eukaryotes. ALKBH5, an m⁶A demethylase, is a promising target, particularly for anticancer drug discovery. However, the development of selective and potent inhibitors of ALKBH5 rather than FTO remains challenging. Herein, we used a targeted covalent inhibition strategy and identified a covalent inhibitor, TD19, which selectively inhibits ALKBH5 compared with FTO demethylase in protein-based and tumor cell-based assays. TD19 irreversibly modifies the residues C100 and C267, preventing ALKBH5 from binding to m⁶A-containing RNA. Moreover, TD19 displays good anticancer efficacy in acute myeloid leukemia and glioblastoma multiforme cell line

SUBMITTER: Lai GQ 

PROVIDER: S-EPMC10989504 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature