Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes

Shota Yanagida, Ayano Satsuka, Sayo Hayashi, Atsushi Ono, Yasunari Kanda

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the anti-hepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was with-drawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addi-tion, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.

Original languageEnglish
Pages (from-to)359-369
Number of pages11
JournalJournal of Toxicological Sciences
Volume46
Issue number8
DOIs
Publication statusPublished - 2021

Keywords

  • Cardiomyocyte
  • Chronic cardiotoxicity
  • Contractility
  • IPS cell
  • Nucleotide analogue

ASJC Scopus subject areas

  • Toxicology

Fingerprint

Dive into the research topics of 'Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes'. Together they form a unique fingerprint.

Cite this