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.
Highlights
Drug discovery projects routinely use tumor-derived or genetically immortalized cell lines and primary cells from experimental animals to assess toxicity of novel compounds (Horvath et al 2016)
The cell type chosen for toxicity screening may influence the results and a wrong choice can lead to misjudgements in lead selection
Archives of Toxicology (2018) 92:2897–2911 cell technology (Takahashi et al 2007; Yu et al 2007), enables the production of almost any human cell type in the laboratory. This provides a unique possibility to carry out drug screening and toxicity studies using differentiated human cells that cannot be readily obtained from living persons, such as cardiomyocytes and neurons, and eliminates the influence of interspecies differences
Summary
Drug discovery projects routinely use tumor-derived or genetically immortalized cell lines and primary cells from experimental animals to assess toxicity of novel compounds (Horvath et al 2016). More precise in vitro toxicity assessment using human cell models that more closely resemble physiological cell types is, urgently needed to improve the validity of results and to reduce drug discovery costs and the use of experimental animals (Sison-Young et al 2012). Archives of Toxicology (2018) 92:2897–2911 cell (hiPSC) technology (Takahashi et al 2007; Yu et al 2007), enables the production of almost any human cell type in the laboratory This provides a unique possibility to carry out drug screening and toxicity studies using differentiated human cells that cannot be readily obtained from living persons, such as cardiomyocytes and neurons, and eliminates the influence of interspecies differences. Pluripotent stem cells have been accepted as a validated model for evaluating reproductive and developmental toxicity in vitro (Seiler and Spielmann 2011)
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