Structure-based design of a potent and selective YTHDC1 ligand
Title | Structure-based design of a potent and selective YTHDC1 ligand |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Zálešák F., Nai F., Herok M., Bochenkova E., Bedi R.K, Li Y., Errani F., Caflisch A. |
Journal | Journal of Medicinal Chemistry |
Volume | 67 |
Issue | 11 |
Pagination | 9516-9535 |
Date Published | 2024 May 24 |
Type of Article | Research Article |
Abstract | N6-Adenosine methylation (m6A) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the nucleus of the cell. Here we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor 40 which shows an equilibrium dissociation constant (Kd) of 49 nM. The crystal structure of the complex (1.6-A resolution) validated the design. Compound 40 is selective against the cytoplasmic m6A-RNA readers YTHDF1-3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO1. For the series of compounds that culminated into ligand 40, the good correlation between the affinity in the biochemical assay and antiproliferative activity in the cellular assay (THP-1) provides evidence of YTHDC1 target engagement in the cell. Thus compound 40 meets chemical probe properties for studying the role of YTHDC1 in AML. |
URL | https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00599 |
DOI | 10.1021/acs.jmedchem.4c00599 |
pubindex | 0297 |
Alternate Journal | J. Med. Chem. |