title: HL005--a new selective PPARγ antagonist specifically inhibits the proliferation of MCF-7.
abstract: Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear transcription factor which is involved in many diseases, such as diabetes, inflammation, dyslipidemia, hypertension, and cancer. Recently, there are many reports showing that PPARγ agonists have preclinical and clinical anticancer activity, with relatively few reports on anticancer effects of PPARγ antagonists. From our compound library, a novel 3-thiazolinone-modified benzoic acid derivative HL005 is found as PPARγ selective ligand through SPR analysis (K(D)=0.21 μM), yeast two-hybrid results suggest that HL005 antagonize the potent PPARγ agonist rosiglitazone-induced recruitment of the coactivator for PPARγ (IC(50)=7.97 μM). Different from the most reported PPARγ antagonist, HL005 can inhibit the proliferation of MCF-7 cell line in a concentration-dependent manner and induce cell cycle arrest at G2/M phase, other than interference with cell adhesion. In order to study the binding mode of this compound, three derivatives are synthesized to get more detail about the structure-activity relationship, molecular docking and the NMR spectra indicate that similar to most PPARγ ligand, the carboxylic acid group is an important moiety for HL005 and contributes strong interaction with PPARγ.
authors.affiliation: Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.forename: Peng
authors.initials: P
authors.lastname: Che
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Shien
authors.initials: S
authors.lastname: Zou
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology*; D019817:Benzoic Acid / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics; D011485:Protein Binding; D013844:Thiazoles / Q000737:chemistry*; D053778:Thiazolidines / Q000494:pharmacology*; D020798:Two-Hybrid System Techniques
chemical_list: C558243:5-(5-(3-chloro-5-ethoxy-4-hydroxybenzylidene)-3-methyl-4-oxothiazolidin-2-ylideneamino)-2-chlorobenzoic acid; D062365:Aminobenzoates; D047495:PPAR gamma; D013844:Thiazoles; D053778:Thiazolidines; D019817:Benzoic Acid