N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, regulates essential post-transcriptional processes. The reader proteins YTHDF2 and YTHDC2 specifically recognize m6A-modified RNAs, acting as central mediators of epitranscriptomic control. We employ computational modeling, structure-based drug design, and biochemical screening to identify lead compounds targeting these readers. In this proposal, we seek synchrotron beamtime to elucidate high-resolution structures of YTHDF2 and YTHDC2 in complex with our lead compounds. These structural insights will guide the optimization of potent, selective chemical probes, enabling visualization of protein–ligand interactions and mechanistic understanding of m6A-dependent regulation. Ultimately, this work will lay the groundwork for targeted therapeutic modulation of dysregulated epitranscriptomic pathways.