Discovery of a PROTAC degrader for METTL3-METTL14 complex.
Abstract
N6-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.
| Authors: | Du W, Huang Y, Chen X, Deng Y, Sun Y, Yang H, Shi Q, Wu F, Liu G, Huang H, Ding J, Huang X, Xu S, |
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| Journal: | Cell Chem Biol;2024Jan18; 31 (1) 177. doi:10.1016/j.chembiol.2023.12.009 |
| Year: | 2024 |
| PubMed: | PMID: 38194973 (Go to PubMed) |