Proteolysis Targeting Chimera Degraders of the METTL3-14 m⁶A-RNA Methyltransferase.

ABSTRACT: Methylation of adenine N6 (m⁶A) is the most frequent RNA modification. On mRNA, it is catalyzed by the METTL3-14 heterodimer complex, which plays a key role in acute myeloid leukemia (AML) and other types of blood cancers and solid tumors. Here, we disclose the first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics protein. For designing the PROTACs, we made use of the crystal structure of the complex of METTL3-14 with a potent and selective small-molecule inhibitor (called UZH2). The optimization of the linker started from a desfluoro precursor of UZH2 whose synthesis is more efficient than that of UZH2. The first nine PROTAC molecules featured PEG- or alkyl-based linkers, but only the latter showed cell penetration. With this information in hand, we synthesiz

SUBMITTER: Errani F 

PROVIDER: S-EPMC10900215 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature