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.