A Stapled Peptide Inhibitor of METTL3-METTL14 for Cancer Therapy

Abstract

AbstractMETTL3, a primary methyltransferase catalyzing RNA m6A modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition, although current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of RNA m6A modification. Among candidate peptides,RM3exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the α-helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysisin vivoindicated thatRSM3induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced uponRSM3treatment, accompanied by increased METTL3 degradation and reduced global RNA methylation levels in twoin vivotumor models. This peptide inhibitor thus exploits a mechanism distinct from other competitive-binding small molecules to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation.