Abstract:
:Selective estrogen receptor degrader (SERD) that acts as not only ER antagonist, but also ER degrader, would be useful for the treatment for drug-resistance ER+ breast cancer. However, most of currently available SERD candidates involve very limited molecular scaffolds and are still in clinical trials. In this study, we introduced a 1,3,5-triazine ring into a homobibenzyl motif extracted from amounts of ER ligands and synthesized sixteen SERDs bearing acrylic acid or acrylic amide side chains that possess both ERα antagonism and degradation properties. And all compounds were screened for their anti-proliferative activity against ER+ MCF-7 and Ishikawa cell lines. Among them, compound XHA1614 displayed potent growth inhibition activity against MCF-7 and Ishikawa cells with IC50 values of 3.15 μM and 3.11 μM, respectively. Moreover, XHA1614 could dramatically degrade ER level at 1 nM in a Western blotting assay and afforded an outstanding antagonistic activity via suppressing the expression of progesterone receptor messenger RNA in MCF-7 cells in a RT-PCR assay. Further molecular docking and dynamic simulation on properly selected derivative furnished insights into its binding profile within ERα. Our findings suggest that the 1,3,5-triazine core was a feasible alternative to currently reported SERD scaffold, and provide information that will be useful for further development of promising SERDs candidates for breast cancer therapies.
journal_name
Bioorg Chemjournal_title
Bioorganic chemistryauthors
Lu X,Huang A,Xiao M,Sun L,Mao J,Luo G,Xiang Hdoi
10.1016/j.bioorg.2020.103666subject
Has Abstractpub_date
2020-04-01 00:00:00pages
103666eissn
0045-2068issn
1090-2120pii
S0045-2068(19)31334-3journal_volume
97pub_type
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journal_title:Bioorganic chemistry
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pub_type: 杂志文章
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更新日期:2008-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:2020-07-01 00:00:00
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pub_type: 杂志文章
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更新日期:2019-11-01 00:00:00