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

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Karhu , S T , Välimäki , M J , Jumppanen , A M , Kinnunen , S M , Pohjolainen , L M , Leigh , R S , Auno , A S , Földes , G , Boije af Gennäs , P G , Yli-Kauhaluoma , J T , Ruskoaho , H J & Talman , V 2018 , ' Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds ' , Archives of Toxicology , vol. 92 , no. 9 , pp. 2897-2911 . https://doi.org/10.1007/s00204-018-2257-1

Title: Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds
Author: Karhu, Suvi Tuuli; Välimäki, Mika Juhani; Jumppanen, Antti Mikael; Kinnunen, Sini Marketta; Pohjolainen, Lotta Matilda; Leigh, Robert Scott; Auno, Atte Samuli; Földes, Gábor; Boije af Gennäs, Per Gustav; Yli-Kauhaluoma, Jari Tapani; Ruskoaho, Heikki Juhani; Talman, Virpi
Contributor organization: Regenerative cardiac pharmacology
Regenerative pharmacology group
Faculty of Pharmacy
Pharmaceutical Design and Discovery group
Division of Pharmacology and Pharmacotherapy
Timo Pyry Juhani Otonkoski / Principal Investigator
Division of Pharmaceutical Chemistry and Technology
Drug Research Program
Jari Yli-Kauhaluoma / Principal Investigator
Date: 2018-09
Language: eng
Number of pages: 15
Belongs to series: Archives of Toxicology
ISSN: 0340-5761
DOI: https://doi.org/10.1007/s00204-018-2257-1
URI: http://hdl.handle.net/10138/240364
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 A mu M 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.
Subject: 317 Pharmacy
Toxicity screening
High-content analysis
Structure-toxicity relationship
Stem cells
Cardiomyocytes
Isoxazole derivatives
TRANSCRIPTION FACTORS
DNA-DAMAGE
ON-WATER
GATA4
HEART
CARDIOMYOCYTES
ISOXAZOLES
CYCLOADDITIONS
CARDIOGENESIS
REGENERATION
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion


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