Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery.
Sci Rep
; 11(1): 1121, 2021 01 13.
Article
in En
| MEDLINE
| ID: mdl-33441849
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyridines
/
CCAAT-Enhancer-Binding Proteins
/
Ubiquitin-Protein Ligases
/
Small Molecule Libraries
/
Drug Discovery
/
Tudor Domain
Type of study:
Prognostic_studies
Language:
En
Journal:
Sci Rep
Year:
2021
Document type:
Article
Affiliation country: