Discovery of USP7 small-molecule allosteric inhibitors.
Bioorg Med Chem Lett
; 30(20): 127471, 2020 10 15.
Article
in En
| MEDLINE
| ID: mdl-32781219
ABSTRACT
Ubiquitin specific protease-7 (USP7) is considered an attractive target for cancer therapy by promoting degradation of the tumor suppressor p53 and negatively affecting the immune response to tumors. However, the development of selective non-covalent USP7 inhibitors has proven challenging. In this work we report the NMR characterization of a weak binder from SPR screening of an in-house fragment library which reveals that it binds to the allosteric palm site of the catalytic domain. Molecular modeling combined with 1HNMR saturation transfer difference and NOESY experiments enabled structure-based design of additional compounds showing IC50 values in the low-micromolar range with good selectivity over the closest homolog USP47. The most potent analogue represents a promising starting point for the development of novel, selective USP7 inhibitors.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Small Molecule Libraries
/
Drug Discovery
/
Ubiquitin-Specific Peptidase 7
/
Amides
Limits:
Humans
Language:
En
Year:
2020
Type:
Article