Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2018-09
Date Acceptance
2018-07-04
Citation
Archives of Toxicology, 2018, 92 (9), pp.2897-2911
ISSN
0340-5761
Publisher
Springer Verlag
Start Page
2897
End Page
2911
Journal / Book Title
Archives of Toxicology
Volume
92
Issue
9
Copyright Statement
© 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Sponsor
Medical Research Council (MRC)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29987409
PII: 10.1007/s00204-018-2257-1
Grant Number
WHCF_P73095
Subjects
Cardiomyocytes
High-content analysis
Isoxazole derivatives
Stem cells
Structure–toxicity relationship
Toxicity screening
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2018-07-09