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

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. The most potent PROTAC, 4j, demonstrated sub-micromolar degradation potency in MV4.11 cells with DC50 values of 0.44 µM for METTL3 and 0.13 µM for METTL14. Notably, 4j showed enhanced cytotoxicity in MV4.11 cells compared to well-validated METTL3 inhibitors, underscoring the therapeutic potential of targeted degradation of the METTL3/METTL14 complex in AML.