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<p>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.</p>

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Development of a novel therapy for systolic heart failure

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月4日

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  • Corey Pollock,
  • Xilun Wang,
  • Hussam Alsaraji,
  • Joseph Menassa,
  • George Mbogo,
  • Dimuthu Angage,
  • Benjamin Richards,
  • Jason Glab,
  • Keshava K Datta,
  • Liana Theodoridis,
  • Steve Petrovski,
  • Daniel Donner,
  • Yuvixza Lizarme-Salas,
  • Xiao-Jun Du,
  • Michael Foley,
  • Brian J Smith,
  • Belinda Abbott,
  • Hamsa Puthalakath

摘要

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.