Protein structure-based design of chemical probes for the m6A-mRNA reader YTHDC1

N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger RNA, plays a crucial role in numerous biological processes. m6A reader proteins, which recognize and interpret these modifications, serve as key mediators in epitranscriptomic regulation. Using computational modeling, structure-based drug design, and high-throughput screening techniques we have identified lead compounds against the modulators of m6A. With this proposal we aim to further develop our lead compounds into highly potent and selective chemical probes targeting the nuclear m6A-mRNA reader protein YTHDC1. These chemical probes illuminate protein-RNA interactions, revealing epitranscriptomic regulation mechanisms. By manipulating m6A reader proteins, they enable targeted therapies for diseases driven by dysregulated epitranscriptomic processes.