Language
English
Publication Date
1-13-2021
Journal
Scientific Reports
DOI
10.1038/s41598-020-80588-4
PMID
33441849
PMCID
PMC7806715
PubMedCentral® Posted Date
1-13-2021
PubMedCentral® Full Text Version
Post-print
Abstract
Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recognizes the heterochromatin-associated histone mark H3K9me3 and supports intramolecular contacts with other regions of UHRF1. Using both binding-based and function-based screens of a ~ 2300-fragment library in parallel, we identified 2,4-lutidine as a hit for follow-up NMR and X-ray crystallography studies. Unlike previous reported ligands, 2,4-lutidine binds to two binding pockets that are in close proximity on TTD and so has the potential to be evolved into more potent inhibitors using a fragment-linking strategy. Our study provides a useful starting point for developing potent chemical probes against UHRF1.
Keywords
Binding Sites, CCAAT-Enhancer-Binding Proteins, Crystallography, X-Ray, Drug Discovery, Histone Code, Histones, Ligands, Magnetic Resonance Spectroscopy, Molecular Structure, Peptide Fragments, Protein Binding, Pyridines, Small Molecule Libraries, Structure-Activity Relationship, Tudor Domain, Ubiquitin-Protein Ligases, Chemical tools, Cancer, Drug screening
Published Open-Access
yes
Recommended Citation
Chang, Lyra; Campbell, James; Raji, Idris O; et al., "Discovery of Small Molecules Targeting the Tandem Tudor Domain of the Epigenetic Factor UHRF1 Using Fragment-Based Ligand Discovery" (2021). Faculty and Staff Publications. 380.
https://digitalcommons.library.tmc.edu/baylor_docs/380
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biology Commons, Oncology Commons