The ARumenamide AR-788 suppresses the transient outward current in human iPSC-derived right-ventricular Brugada cardioids
Abstract
Brugada syndrome (BrS) is an inherited arrhythmia disorder with limited drug therapy, quinidine being the principal agent. Loss-of-function variants in SCN5A reduce the cardiac sodium current (INa), but the arrhythmogenic imbalance also depends on the transient outward potassium current (Ito). Here we generated human induced pluripotent stem cell-derived cardioids with right-ventricular identity from a patient carrying an SCN5A frameshift variant (p.A665Gfs*16) and characterised them by patch-clamp and optical mapping. BrS cardioids showed 60% lower peak INa, more than doubled Ito, 38% slower conduction and 76% longer spontaneous cycle length. We then tested AR-788, a benzylaminothiazole-benzimidazole carboxamide of the ARumenamide class. In wild-type (WT) cardiomyocytes AR-788 inhibited Ito concentration-dependently (12%, 30% and 42% at 5, 10 and 20 uM; extrapolated IC50 25.4 uM), and at 10 uM it returned BrS Ito to the level of untreated WT cells (21.71 vs 21.48 pA/pF, p = 0.9716) without reducing INa. It also reduced the rapid delayed-rectifier current (IKr) tail current by 40%, a liability requiring formal proarrhythmia profiling. These data identify AR-788 as an Ito-suppressing member of the ARumenamide class and provide proof of concept that a small molecule can correct the potassium-current excess in a human BrS model.
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BibTeX
@misc{gueret2026arumenamide,
title = {{The ARumenamide AR-788 suppresses the transient outward current in human iPSC-derived right-ventricular Brugada cardioids}},
author = {Yohan Gueret and Aurore Girardeau and Sarah Godin and Maureen Choteau-Bodor and Jerome Montnach and Guillaume Lamirault and Nathalie Gaborit and Mena Abdelsayed},
howpublished = {HAL},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.26364857},
url = {https://hal.science/hal-05792967v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - The ARumenamide AR-788 suppresses the transient outward current in human iPSC-derived right-ventricular Brugada cardioids
AU - Yohan Gueret
AU - Aurore Girardeau
AU - Sarah Godin
AU - Maureen Choteau-Bodor
AU - Jerome Montnach
AU - Guillaume Lamirault
AU - Nathalie Gaborit
AU - Mena Abdelsayed
PY - 2026
DA - 2026/10/06
PB - HAL
DO - 10.64898/2026.10.06.26364857
UR - https://hal.science/hal-05792967v1
AB - Brugada syndrome (BrS) is an inherited arrhythmia disorder with limited drug therapy, quinidine being the principal agent. Loss-of-function variants in SCN5A reduce the cardiac sodium current (INa), but the arrhythmogenic imbalance also depends on the transient outward potassium current (Ito). Here we generated human induced pluripotent stem cell-derived cardioids with right-ventricular identity from a patient carrying an SCN5A frameshift variant (p.A665Gfs*16) and characterised them by patch-clamp and optical mapping. BrS cardioids showed 60% lower peak INa, more than doubled Ito, 38% slower conduction and 76% longer spontaneous cycle length. We then tested AR-788, a benzylaminothiazole-benzimidazole carboxamide of the ARumenamide class. In wild-type (WT) cardiomyocytes AR-788 inhibited Ito concentration-dependently (12%, 30% and 42% at 5, 10 and 20 uM; extrapolated IC50 25.4 uM), and at 10 uM it returned BrS Ito to the level of untreated WT cells (21.71 vs 21.48 pA/pF, p = 0.9716) without reducing INa. It also reduced the rapid delayed-rectifier current (IKr) tail current by 40%, a liability requiring formal proarrhythmia profiling. These data identify AR-788 as an Ito-suppressing member of the ARumenamide class and provide proof of concept that a small molecule can correct the potassium-current excess in a human BrS model.
ER -