University of Oulu

Karhu, S.T., Välimäki, M.J., Jumppanen, M. et al. Arch Toxicol (2018) 92: 2897.

Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds

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Author: Karhu, S. Tuuli1; Välimäki, Mika J.1,2; Jumppanen, Mikael3;
Organizations: 1Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
2Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland
3Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
4National Heart and Lung Institute, Imperial College London, London, UK
5Heart and Vascular Center, Semmelweis University, Budapest, Hungary
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 8.9 MB)
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Language: English
Published: Springer Nature, 2018
Publish Date: 2019-06-28


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.

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Series: Archives of toxicology
ISSN: 0340-5761
ISSN-E: 1432-0738
ISSN-L: 0340-5761
Volume: 92
Issue: 9
Pages: 2897 - 2911
DOI: 10.1007/s00204-018-2257-1
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: The research was funded by the Finnish Funding Agency for Innovation (Tekes, 3iRegeneration, Project 40395/13), the Academy of Finland (Project 2666621), the Finnish Foundation for Cardiovascular Research, and the Sigrid Jusélius Foundation.
Copyright information: © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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.