Development of a novel therapy for systolic heart failure

Heart failure presents a critical health challenge with a 5-year mortality rate of up to 50%. Conventional treatments often lead to bradycardia or hypotension due to their impact on patient hemodynamics. To address this issue, we utilized high-throughput drug screening combined with structure-activity relationship-based medicinal chemistry to develop a novel drug-like compound that effectively blocks the β-adrenergic receptor (β-AR) mediated apoptosis pathway. This compound demonstrated both safety and efficacy in pre-clinical mouse models without adversely affecting cardiac output. Through thermal proteome profiling mass spectrometry, we identified the compound's target as Wdr3, a regulator of the Hippo signaling pathway. This target identification was further validated using CRISPR-based knockout experiments. Our findings provide a valuable framework for the development of hemodynamically neutral therapies aimed at treating systolic heart failure.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-08-04
DOI
https://doi.org/10.1038/s44321-025-00284-6
Primary Topic
Cardiac electrophysiology and arrhythmias
Type
article
Field-Weighted Citation Impact
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article

Development of a novel therapy for systolic heart failure

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Development of a novel therapy for systolic heart failure

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article en

Abstract

Heart failure presents a critical health challenge with a 5-year mortality rate of up to 50%. Conventional treatments often lead to bradycardia or hypotension due to their impact on patient hemodynamics. To address this issue, we utilized high-throughput drug screening combined with structure-activity relationship-based medicinal chemistry to develop a novel drug-like compound that effectively blocks the β-adrenergic receptor (β-AR) mediated apoptosis pathway. This compound demonstrated both safety and efficacy in pre-clinical mouse models without adversely affecting cardiac output. Through thermal proteome profiling mass spectrometry, we identified the compound's target as Wdr3, a regulator of the Hippo signaling pathway. This target identification was further validated using CRISPR-based knockout experiments. Our findings provide a valuable framework for the development of hemodynamically neutral therapies aimed at treating systolic heart failure.

EMBO Molecular MedicineVol. 17(9)
Baker Heart and Diabetes Institute (AU), La Trobe University (AU)
Good health and well-being
Openalex Percentile: Top 69%
Cardiac electrophysiology and arrhythmias
DOIOpen Access PDFOpenAlex
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