Abstract
| Original language | English |
|---|---|
| Journal | Archives of Toxicology |
| Volume | 92 |
| Issue number | 9 |
| Pages (from-to) | 2897-2911 |
| Number of pages | 15 |
| ISSN | 0340-5761 |
| DOIs | |
| Publication status | Published - 30 Aug 2018 |
| MoE publication type | A1 Journal article-refereed |
Fields of Science
- 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
Cite this
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Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds. / 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.
In: Archives of Toxicology, Vol. 92, No. 9, 30.08.2018, p. 2897-2911.Research output: Contribution to journal › Article › Scientific › peer-review
TY - JOUR
T1 - Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds
AU - Karhu, Suvi Tuuli
AU - Välimäki, Mika Juhani
AU - Jumppanen, Antti Mikael
AU - Kinnunen, Sini Marketta
AU - Pohjolainen, Lotta Matilda
AU - Leigh, Robert Scott
AU - Auno, Atte Samuli
AU - Földes, Gábor
AU - Boije af Gennäs, Per Gustav
AU - Yli-Kauhaluoma, Jari Tapani
AU - Ruskoaho, Heikki Juhani
AU - Talman, Virpi
PY - 2018/8/30
Y1 - 2018/8/30
N2 - 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.
AB - 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.
KW - 317 Pharmacy
KW - Toxicity screening
KW - High-content analysis
KW - Structure-toxicity relationship
KW - Stem cells
KW - Cardiomyocytes
KW - Isoxazole derivatives
KW - TRANSCRIPTION FACTORS
KW - DNA-DAMAGE
KW - ON-WATER
KW - GATA4
KW - HEART
KW - CARDIOMYOCYTES
KW - ISOXAZOLES
KW - CYCLOADDITIONS
KW - CARDIOGENESIS
KW - REGENERATION
U2 - 10.1007/s00204-018-2257-1
DO - 10.1007/s00204-018-2257-1
M3 - Article
VL - 92
SP - 2897
EP - 2911
JO - Archives of Toxicology
JF - Archives of Toxicology
SN - 0340-5761
IS - 9
ER -