Jin-zi Ji1, Ke-jing Lao2, Jie Hu1, Tao Pang3, Zhen-zhou Jiang4, Hao-liang Yuan5, Jing-shan Miao1, Xin Chen1, Shan-shan Ning2, Hua Xiang2, Yu-meng Guo1, Ming Yan3, Lu-yong Zhang6. 1. Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China. 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. 3. 1] Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China [2] Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China. 4. 1] Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China [2] Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China. 5. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing 210009, China. 6. 1] Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China [2] State Key laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Abstract
AIM: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). METHODS: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. RESULTS: The Z' value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. CONCLUSION: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.
AIM: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). METHODS: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. RESULTS: The Z' value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. CONCLUSION:XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.
Authors: J Murray; O E Young; L Renshaw; S White; L Williams; D B Evans; J St J Thomas; M Dowsett; J M Dixon Journal: Breast Cancer Res Treat Date: 2008-04-26 Impact factor: 4.872
Authors: Marc van Dijk; Antonius M Ter Laak; Jörg D Wichard; Luigi Capoferri; Nico P E Vermeulen; Daan P Geerke Journal: J Chem Inf Model Date: 2017-08-23 Impact factor: 4.956