Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger.
ACS Chem Biol
; 9(12): 2864-74, 2014 Dec 19.
Article
in En
| MEDLINE
| ID: mdl-25323450
ABSTRACT
The Pygo-BCL9 complex is a chromatin reader, facilitating ß-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the BCL9 HD1 domain. Here, we report the first use of fragment-based screening by NMR to identify small molecules that block protein-protein interactions by a PHD finger. This led to the discovery of a set of benzothiazoles that bind to a cleft emanating from the PHD-HD1 interface, as defined by X-ray crystallography. Furthermore, we discovered a benzimidazole that docks into the H3K4me specificity pocket and displaces the native H3K4me peptide from the PHD finger. Our study demonstrates the ligandability of the Pygo-BCL9 complex and uncovers a privileged scaffold as a template for future development of lead inhibitors of oncogenesis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Benzimidazoles
/
Histones
/
Adaptor Proteins, Signal Transducing
/
Benzothiazoles
/
Neoplasm Proteins
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
ACS Chem Biol
Year:
2014
Document type:
Article
Affiliation country:
United kingdom