This study reports the development of proteolysis targeting chimeras (PROTACs) for the METTL3–14 m6A-RNA methyltransferase, a key player in various cancers. The research team utilized the crystal structure of the METTL3–14 complex with a potent inhibitor, UZH2, to design PROTACs. They optimized the linker by starting with a desfluoro precursor of UZH2, which is more efficient to synthesize. The first nine PROTACs featured PEG or alkyl-based linkers, but only the latter showed cell penetration. Based on this information, they synthesized 26 PROTACs using UZH2 and various alkyl linkers. The formation of the ternary complex was validated by FRET-based biochemical assays and in vitro ubiquitination assays. The PROTACs 14, 20, 22, 24, and 30 showed significant degradation of METTL3 and/or METTL14 in MOLM-13 cells and other AML and prostate cancer cell lines. These PROTACs demonstrated substantial degradation of METTL3 and METTL14, indicating their potential as tools for targeted protein degradation. The study also highlights the importance of linker length and rigidity in achieving effective degradation. The results suggest that PROTACs could be valuable in targeting METTL3–14 in various cancers. The synthesis of these PROTACs involved various chemical reactions and optimization strategies to achieve the desired properties. The study provides insights into the design and optimization of PROTACs for targeting specific proteins, which could have implications for the treatment of various cancers.This study reports the development of proteolysis targeting chimeras (PROTACs) for the METTL3–14 m6A-RNA methyltransferase, a key player in various cancers. The research team utilized the crystal structure of the METTL3–14 complex with a potent inhibitor, UZH2, to design PROTACs. They optimized the linker by starting with a desfluoro precursor of UZH2, which is more efficient to synthesize. The first nine PROTACs featured PEG or alkyl-based linkers, but only the latter showed cell penetration. Based on this information, they synthesized 26 PROTACs using UZH2 and various alkyl linkers. The formation of the ternary complex was validated by FRET-based biochemical assays and in vitro ubiquitination assays. The PROTACs 14, 20, 22, 24, and 30 showed significant degradation of METTL3 and/or METTL14 in MOLM-13 cells and other AML and prostate cancer cell lines. These PROTACs demonstrated substantial degradation of METTL3 and METTL14, indicating their potential as tools for targeted protein degradation. The study also highlights the importance of linker length and rigidity in achieving effective degradation. The results suggest that PROTACs could be valuable in targeting METTL3–14 in various cancers. The synthesis of these PROTACs involved various chemical reactions and optimization strategies to achieve the desired properties. The study provides insights into the design and optimization of PROTACs for targeting specific proteins, which could have implications for the treatment of various cancers.