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

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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.　©　2018　Elsevier　Masson　SAS

Keyword：

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

Community：

[ 1 ] [Lin, Y.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
[ 2 ] [Liu, R.]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China
[ 3 ] [Zhao, P.]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China
[ 4 ] [Ye, J.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
[ 5 ] [Zheng, Z.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
[ 6 ] [Huang, J.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
[ 7 ] [Zhang, Y.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
[ 8 ] [Gao, Y.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
[ 9 ] [Chen, H.]Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
[ 10 ] [Liu, S.]Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
[ 11 ] [Liu, S.]Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
[ 12 ] [Zhou, J.]Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
[ 13 ] [Chen, C.]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan 650223, China
[ 14 ] [Chen, H.]College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China

Reprint 's Address：

[Chen, H.]College of Chemistry, Fuzhou UniversityChina

Email：

chenhaij@gmail.com

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Source ：

European Journal of Medicinal Chemistry

ISSN： 0223-5234

Year： 2018

Volume： 146

Page： 354-367

4 . 8 3 3

JCR@2018

6 . 0 0 0

JCR@2023

ESI HC Threshold：209

JCR Journal Grade：1

CAS Journal Grade：1

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WoS CC Cited Count：

SCOPUS Cited Count： 15

ESI Highly Cited Papers on the List： 0 Unfold All

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Chinese Cited Count：

30 Days PV： 0

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