PROTAC degraders of the METTL3-14 m6A-RNA methyltransferase

Methylation of adenine N6 (m6A) is the most frequent RNA modification. On mRNA, it is catalyzed by the METTL3-14 heterodimer complex which plays a key role in acute myeloid leukemia (AML) and other types of blood cancers and solid tumors. Here we disclose the first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics target. For design-ing the PROTACs we made use of the crystal structure of the complex of METTL3-14 with a potent and selective small-molecule inhibitor (called UZH2). The optimization of the linker started from a desfluoro precursor of UZH2 whose syn-thesis is more efficient than the one of UZH2. The first nine PROTAC molecules featured PEG- or alkyl-based linkers but only the latter showed cell penetration. With this information in hand, we synthesized 26 PROTACs based on UZH2 and alkylic linkers of different lengths and rigidity. The formation of the ternary complex was validated by a FRET-based biochemical assay and an in vitro ubiquitination assay. Three PROTACs with three different rigid extensions of UZH2 showed 50% or higher degradation of METTL3 and METTL14 measured by Western blot in MOLM-13. Substantial degra-dation was measured also on three others AML cell lines and the prostate cancer cell line PC3.