Abstract
Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers currently with a lack of targeted therapeutic drugs. Accumulating evidence supports that KLF5 represents a novel therapeutic target for the treatment of basal TNBC. Our previous studies revealed that mifepristone is capable of suppressing TNBC cell proliferation and promoting cancer cell apoptosis by inhibiting KLF5 expression. Nevertheless, its anticancer efficacy is only modest with high dose. Moreover, its main metabolite N-desmethyl mifepristone with the removal of one methyl moiety results in a significant loss of antiproliferative activity, indicating an important pharmacophore domain around this methyl moiety. To improve the pharmacokinetic properties including metabolic stability and enhance the anticancer activities, a focused compound library by altering this sensitive metabolic region of mifepristone has been designed and synthesized for scaffold repurposing and structural optimization. Compound 17 (FZU-00,004) has been identified with an attractive anticancer profile against TNBC via suppressing KLF5 expression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 354-367 |
| Number of pages | 14 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 146 |
| DOIs | |
| State | Published - Feb 25 2018 |
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Keywords
- KLF5 expression
- Mifepristone derivatives
- Sensitive metabolic region
- Triple-negative breast cancer
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
Cite this
Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer. / Lin, Yuqi; Liu, Rong; Zhao, Ping; Ye, Jinxiang; Zheng, Zheng; Huang, Jingan; Zhang, Yingying; Gao, Yu; Chen, Haiying; Liu, Suling; Zhou, Jia; Chen, Ceshi; Chen, Haijun.
In: European Journal of Medicinal Chemistry, Vol. 146, 25.02.2018, p. 354-367.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer
AU - Lin, Yuqi
AU - Liu, Rong
AU - Zhao, Ping
AU - Ye, Jinxiang
AU - Zheng, Zheng
AU - Huang, Jingan
AU - Zhang, Yingying
AU - Gao, Yu
AU - Chen, Haiying
AU - Liu, Suling
AU - Zhou, Jia
AU - Chen, Ceshi
AU - Chen, Haijun
PY - 2018/2/25
Y1 - 2018/2/25
N2 - Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers currently with a lack of targeted therapeutic drugs. Accumulating evidence supports that KLF5 represents a novel therapeutic target for the treatment of basal TNBC. Our previous studies revealed that mifepristone is capable of suppressing TNBC cell proliferation and promoting cancer cell apoptosis by inhibiting KLF5 expression. Nevertheless, its anticancer efficacy is only modest with high dose. Moreover, its main metabolite N-desmethyl mifepristone with the removal of one methyl moiety results in a significant loss of antiproliferative activity, indicating an important pharmacophore domain around this methyl moiety. To improve the pharmacokinetic properties including metabolic stability and enhance the anticancer activities, a focused compound library by altering this sensitive metabolic region of mifepristone has been designed and synthesized for scaffold repurposing and structural optimization. Compound 17 (FZU-00,004) has been identified with an attractive anticancer profile against TNBC via suppressing KLF5 expression.
AB - Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers currently with a lack of targeted therapeutic drugs. Accumulating evidence supports that KLF5 represents a novel therapeutic target for the treatment of basal TNBC. Our previous studies revealed that mifepristone is capable of suppressing TNBC cell proliferation and promoting cancer cell apoptosis by inhibiting KLF5 expression. Nevertheless, its anticancer efficacy is only modest with high dose. Moreover, its main metabolite N-desmethyl mifepristone with the removal of one methyl moiety results in a significant loss of antiproliferative activity, indicating an important pharmacophore domain around this methyl moiety. To improve the pharmacokinetic properties including metabolic stability and enhance the anticancer activities, a focused compound library by altering this sensitive metabolic region of mifepristone has been designed and synthesized for scaffold repurposing and structural optimization. Compound 17 (FZU-00,004) has been identified with an attractive anticancer profile against TNBC via suppressing KLF5 expression.
KW - KLF5 expression
KW - Mifepristone derivatives
KW - Sensitive metabolic region
KW - Triple-negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85041637039&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041637039&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.01.056
DO - 10.1016/j.ejmech.2018.01.056
M3 - Article
VL - 146
SP - 354
EP - 367
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -