Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors.
Bioorg Med Chem Lett
; 30(5): 126957, 2020 03 01.
Article
in En
| MEDLINE
| ID: mdl-31959420
ABSTRACT
Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the "tail" region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2WT IC50 = 22.0 nM). Compound 9b inhibited the proliferation of WSU-DLCL2 and SU-DHL-4 cell lines (IC50 = 1.61 µM and 2.34 µM, respectively). The biological evaluation showed that 9b was a potent inhibitor for wild-type EZH2 and greatly reduced the overall levels of H3K27me3 in a concentration-dependent manner. Further study indicated that 9b could significantly induce apoptosis of SU-DHL-4 cells. These findings indicated that 9b would be an attractive lead compound for further optimization and evaluation.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Stilbenes
/
Enzyme Inhibitors
/
Enhancer of Zeste Homolog 2 Protein
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2020
Type:
Article
Affiliation country:
China