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Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors.

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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

He H,Hu X,Teng F,Liu Z,Zhang Q,Feng Z,Feng Q,Yu L

doi

10.1016/j.bmcl.2020.126957

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

126957

issue

5

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30010-X

journal_volume

30

pub_type

杂志文章

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