Development of a novel therapy for systolic heart failure

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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Fibroblast

DISEASE(S): Disease Free

SUBMITTER: Rohan Lowe  

LAB HEAD: Hamsa Puthalakath

PROVIDER: PXD065822 | Pride | 2025-09-15

REPOSITORIES: Pride