CardioMotion: identification of functional and structural cardiotoxic liabilities in small molecules through brightfield kinetic imaging.

Autor:	Stebbeds W; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK., Raniga K; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK.; The Biodiscovery Institute, University of Nottingham, Nottingham, NG7 2RD, UK., Standing D; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK., Wallace I; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK., Bayliss J; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK., Brown A; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK., Kasprowicz R; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK., Dalmas Wilk D; In vitro in vivo translation, GSK, Upper Providence, PA 19426, USA., Deakyne J; In vitro in vivo translation, GSK, Upper Providence, PA 19426, USA., Clements P; In vitro in vivo translation, GSK, Ware, SG12 0DJ, UK., Chaudhary KW; In vitro in vivo translation, GSK, Upper Providence, PA 19426, USA., Rossman EI; In vitro in vivo translation, GSK, Upper Providence, PA 19426, USA., Bahinski A; In vitro in vivo translation, GSK, Upper Providence, PA 19426, USA., Francis J; Screening Profiling and Mechanistic Biology, GSK, Stevenage, SG1 2NY, UK.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2023 Aug 29; Vol. 195 (1), pp. 61-70.
DOI:	10.1093/toxsci/kfad065
Abstrakt:	Cardiovascular toxicity is an important cause of drug failures in the later stages of drug development, early clinical safety assessment, and even postmarket withdrawals. Early-stage in vitro assessment of potential cardiovascular liabilities in the pharmaceutical industry involves assessment of interactions with cardiac ion channels, as well as induced pluripotent stem cell-derived cardiomyocyte-based functional assays, such as calcium flux and multielectrode-array assays. These methods are appropriate for the identification of acute functional cardiotoxicity but structural cardiotoxicity, which manifests effects after chronic exposure, is often only captured in vivo. CardioMotion is a novel, label-free, high throughput, in vitro assay and analysis pipeline which records and assesses the spontaneous beating of cardiomyocytes and identifies compounds which impact beating. This is achieved through the acquisition of brightfield images at a high framerate, combined with an optical flow-based python analysis pipeline which transforms the images into waveform data which are then parameterized. Validation of this assay with a large dataset showed that cardioactive compounds with diverse known direct functional and structural mechanisms-of-action on cardiomyocytes are identified (sensitivity = 72.9%), importantly, known structural cardiotoxins also disrupt cardiomyocyte beating (sensitivity = 86%) in this method. Furthermore, the CardioMotion method presents a high specificity of 82.5%. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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