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HL005--a new selective PPARγ antagonist specifically inhibits the proliferation of MCF-7
Weiqiang Lu1, Peng Che, Yanyan Zhang
1Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
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.
Insights
A novel compound, HL005, acts as a Peroxisome proliferator-activated receptor-γ (PPARγ) antagonist. It inhibits cancer cell proliferation and induces cell cycle arrest, offering a new avenue for cancer therapy.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor implicated in various diseases, including cancer.
- While PPARγ agonists show anticancer potential, research on PPARγ antagonists is less extensive.
Purpose of the Study:
- To identify and characterize novel PPARγ antagonists with potential anticancer activity.
- To investigate the mechanism of action of a novel compound, HL005, as a PPARγ antagonist.
Main Methods:
- Surface Plasmon Resonance (SPR) and yeast two-hybrid assays were used to identify and validate HL005 as a PPARγ selective ligand and antagonist.
- MCF-7 cell proliferation assays and cell cycle analysis were performed to assess anticancer effects.
- Structure-activity relationship studies, including synthesis of derivatives, molecular docking, and NMR spectroscopy, were conducted to understand binding modes.
Main Results:
- HL005 was identified as a selective PPARγ ligand (K(D)=0.21 μM) and antagonist (IC(50)=7.97 μM).
- HL005 inhibited MCF-7 cell proliferation in a dose-dependent manner and induced G2/M cell cycle arrest.
- The carboxylic acid group of HL005 is crucial for its interaction with PPARγ, as indicated by SAR studies and molecular docking.
Conclusions:
- HL005 represents a novel PPARγ antagonist with significant anticancer properties.
- Its ability to inhibit cancer cell proliferation and induce cell cycle arrest warrants further investigation for therapeutic applications.
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