Discovery of a PROTAC degrader for METTL3-METTL14 complex.

N 6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions. [Display omitted] • WD6305, a potent METTL3-targeted PROTAC degrader, is developed • WD6305 selectively reduces the METTL3 and METTL14 complex • METTL3 degradation outperforms METTL3 inhibition in AML antiproliferation Du et al. discovered and characterized WD6305, a selective METTL3-targeted PROTAC. This compound effectively and selectively abolishes the METTL3 and METT14 complex. Their findings demonstrate that pharmacological degradation of METTL3-METTL14 complex surpasses its inhibition as a potential anti-leukemic strategy. [ABSTRACT FROM AUTHOR]