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• W2830524461 abstract "Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure–toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10 nM up to 30 µM on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure–toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives." @default.
• W2830524461 created "2018-07-19" @default.
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• W2830524461 date "2018-07-09" @default.
• W2830524461 modified "2023-09-27" @default.
• W2830524461 title "Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds" @default.
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• W2830524461 doi "https://doi.org/10.1007/s00204-018-2257-1" @default.
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