Discovery of CRBN-recruiting PROTAC degraders of the METTL3-METTL14 complex.

ABSTRACT: METTL3 and METTL14, key components of the m⁶A writer complex, are frequently overexpressed in various malignancies, including acute myeloid leukemia (AML), where aberrant methylation has been linked to the upregulation of oncogenic transcription. Therefore, targeting the METTL3/METTL14 complex represents a potential therapeutic approach for AML. Although several METTL3 inhibitors have been discovered, their SAM-competitive mode of action often results in reduced cellular potency, prompting interest in alternative strategies such as targeted protein degradation. In this article, we expand upon reported METTL3/METTL14 complex degraders through exploration of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) from multiple exit vectors of UZH2, a reported METTL3 inhibitor. Th

SUBMITTER: Smith AR 

PROVIDER: S-EPMC12615518 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature