Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer

Yuqi Lin; Rong Liu; Ping Zhao; Jinxiang Ye; Zheng Zheng; Jingan Huang; Yingying Zhang; Yu Gao; Haiying Chen; Suling Liu; Jia Zhou; Ceshi Chen; Haijun Chen

doi:10.1016/j.ejmech.2018.01.056

Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer

Yuqi Lin, Rong Liu, Ping Zhao, Jinxiang Ye, Zheng Zheng, Jingan Huang, Yingying Zhang, Yu Gao, Haiying Chen, Suling Liu, Jia Zhou, Ceshi Chen, Haijun Chen

Pharmacology & Toxicology

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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	https://doi.org/10.1016/j.ejmech.2018.01.056
State	Published - Feb 25 2018

Keywords

KLF5 expression
Mifepristone derivatives
Sensitive metabolic region
Triple-negative breast cancer

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2018.01.056

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title = "Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer",

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.",

keywords = "KLF5 expression, Mifepristone derivatives, Sensitive metabolic region, Triple-negative breast cancer",

author = "Yuqi Lin and Rong Liu and Ping Zhao and Jinxiang Ye and Zheng Zheng and Jingan Huang and Yingying Zhang and Yu Gao and Haiying Chen and Suling Liu and Jia Zhou and Ceshi Chen and Haijun Chen",

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year = "2018",

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doi = "10.1016/j.ejmech.2018.01.056",

language = "English (US)",

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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

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Discovery of novel mifepristone derivatives via suppressing KLF5 expression for the treatment of triple-negative breast cancer

Abstract

Keywords

ASJC Scopus subject areas

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