Structure-Based Design of a Potent and Selective YTHDC1 Ligand.

N-Adenosine methylation (mA) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor , which shows an equilibrium dissociation constant () of 49 nM. The crystal structure of the complex (1.6 Å resolution) validated the design. Compound is selective against the cytoplasmic mA-RNA readers YTHDF1-3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO-1. For the series of compounds that culminated into ligand , the good correlation between the affinity in the biochemical assay and antiproliferative activity in the THP-1 cell line provides evidence of YTHDC1 target engagement in the cell. The binding to YTHDC1 in the cell is further supported by the cellular thermal shift assay. Thus, ligand is a tool compound for studying the role of YTHDC1 in AML.