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.
Original languageEnglish
JournalArchives of Toxicology
Volume92
Issue number9
Pages (from-to)2897-2911
Number of pages15
ISSN0340-5761
DOIs
Publication statusPublished - 30 Aug 2018
MoE publication typeA1 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

@article{c5fd3aa581d04ac59cbe7bd9741a8aad,
title = "Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds",
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.",
keywords = "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",
author = "Karhu, {Suvi Tuuli} and V{\"a}lim{\"a}ki, {Mika Juhani} and Jumppanen, {Antti Mikael} and Kinnunen, {Sini Marketta} and Pohjolainen, {Lotta Matilda} and Leigh, {Robert Scott} and Auno, {Atte Samuli} and G{\'a}bor F{\"o}ldes and {Boije af Genn{\"a}s}, {Per Gustav} and Yli-Kauhaluoma, {Jari Tapani} and Ruskoaho, {Heikki Juhani} and Virpi Talman",
year = "2018",
month = "8",
day = "30",
doi = "10.1007/s00204-018-2257-1",
language = "English",
volume = "92",
pages = "2897--2911",
journal = "Archives of Toxicology",
issn = "0340-5761",
publisher = "Springer-Verlag",
number = "9",

}

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 -