8Q31

Crystal structure of YTHDC1 in complex with Compound 12 (ZA_341)

Summary for 8Q31

• Entry DOI: 10.2210/pdb8q31/pdb
• Descriptor: YTH domain-containing protein 1, 9-[(2-aminophenyl)methyl]-2-chloranyl-~{N}-methyl-purin-6-amine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ythdc1, inhibitor, complex, reader, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 38801.50

Authors

Bedi, R.K.,Zalesak, F.,Caflisch, A. (deposition date: 2023-08-03, release date: 2023-12-06, Last modification date: 2024-06-19)

Primary citation

Zalesak, F.,Nai, F.,Herok, M.,Bochenkova, E.,Bedi, R.K.,Li, Y.,Errani, F.,Caflisch, A.
Structure-Based Design of a Potent and Selective YTHDC1 Ligand.
J.Med.Chem., 67:9516-9535, 2024

PubMed Abstract: 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.

PubMed: 38787793
DOI: 10.1021/acs.jmedchem.4c00599

Experimental method

X-RAY DIFFRACTION (1.32 Å)