Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs.
Eur J Med Chem
; 268: 116264, 2024 Mar 15.
Article
in En
| MEDLINE
| ID: mdl-38412693
ABSTRACT
Nuclear receptor binding SET domain (NSD) proteins are a class of histone lysine methyltransferases and implicated in multiple cancer types with aberrant expression and involvement of cancer related signaling pathways. In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC50 of 0.81 µM and 0.84 µM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung cancer cells, and induces s-phase cell cycle arrest and apoptosis. These data establish our compounds as a valuable tool-kit for the study of the biological roles of NSDs in cancer.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Non-Small-Cell Lung
/
Lung Neoplasms
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2024
Document type:
Article
Affiliation country:
China