Runfola Massimiliano, Sestito Simona, Gul Sheraz, Chiellini Grazia, Rapposelli Simona
Department of Pharmacy, University of Pisa, Pisa, 56126, Italy.
Fraunhofer Institute for Molecular Biology & Applied Ecology - ScreeningPort, Hamburg, Germany.
Data Brief. 2020 Jan 31;29:105206. doi: 10.1016/j.dib.2020.105206. eCollection 2020 Apr.
In order to rapidly identify the phenotypic profile and possible off-target liability effects of novel synthesized thyromimetics for selection of lead compounds for further optimization studies, we performed screening on a new small library of synthetic thyromimetics. A comprehensive panel of early toxicity assays comprising cytotoxicity on 4 different cell lines (osteosarcoma, U2OS; lung fibroblast, hTERT; human breast adenocarcinoma, MCF7; human embryonic kidney, HEK293), ERG liability, cytochrome P450 inhibition (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms), and off-target liability against selected proteins (Aurora B kinase and phosphodiesterase PDE4C1) and epigenetic enzymes (HDAC4, HDAC6, HDAC8, HDAC9 & SIRT7). All the compounds were screened at 10 μM in at least triplicate using well-established assays with readouts in luminescence or fluorescence polarization mode. The raw data were processed using Microsoft Excel and the Z' for each assay was calculated (acceptable Z' >0.40). The processed and normalized data were organized in tables and visualized using spider plots. The results which are reported in the present manuscript can be used in prediction studies of early toxicity and off-target liabilities of other thyromimetics using methods. The data reported herein support our research article entitled "Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-Toxicity analysis" by Runfola M., Sestito S., et al. [1].
为了快速鉴定新型合成甲状腺激素模拟物的表型特征和可能的脱靶效应，以便选择先导化合物进行进一步的优化研究，我们对一个新的合成甲状腺激素模拟物小型文库进行了筛选。进行了一系列全面的早期毒性试验，包括对4种不同细胞系（骨肉瘤细胞系U2OS、人端粒酶逆转录酶永生化肺成纤维细胞系hTERT、人乳腺腺癌细胞系MCF7、人胚肾细胞系HEK293）的细胞毒性、ERG效应、细胞色素P450抑制作用（CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4亚型），以及针对选定蛋白质（极光激酶B和磷酸二酯酶PDE4C1）和表观遗传酶（HDAC4、HDAC6、HDAC8、HDAC9和SIRT7）的脱靶效应。所有化合物均以10 μM的浓度进行筛选，至少一式三份，使用成熟的检测方法，检测结果以发光或荧光偏振模式读取。原始数据使用Microsoft Excel进行处理，并计算每个检测的Z'值（可接受的Z' >0.40）。处理后的归一化数据整理成表格，并使用蜘蛛图进行可视化展示。本手稿中报告的结果可用于使用相关方法预测其他甲状腺激素模拟物的早期毒性和脱靶效应。本文报告的数据支持我们的研究文章《通过ADME-毒性分析对新型TRβ选择性激动剂的设计、合成及生物学评价》，作者为Runfola M.、Sestito S.等人[1]。
