<i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m<sup>6</sup>A regulation machinery, is a key player in a variety of diseases including several types of cancer, type 2 diabetes, and viral infections. Here we report on a protein crystallography-based medicinal chemistry optimization of a METTL3 hit compound that has resulted in a 1400-fold potency improvement (IC<sub>50</sub> of 5 nM for the lead compound <b>22</b> (<b>UZH2</b>) in a time-resolved Förster resonance energy transfer (TR-FRET) assay). The series has favorable ADME properties as physicochemical characteristics were taken into account during hit optimization. <b>UZH2</b> shows target engagement in cells and is able to reduce the m<sup>6</sup>A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.