ArticleFrontiers in pharmacology2025
Off-target autophagy disruption associated with a novel liver toxicity in dogs for a highly basic heterobifunctional protein degrader.
Article in Frontiers in pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: The observation of hepatobiliary toxicity in a repeat-dose Good Laboratory Practice-compliant dog toxicology study was a primary driver for the deprioritization of a preclinical heterobifunctional protein degrader candidate, Compound X. The pathology of large bile duct epithelial hyperplasia was novel and its pathogenesis unknown. Methods: In this study, a thorough characterization and mechanistic investigation are presented with both short-term exploratory animal studies and Results: Proteome profiling and high-content imaging highlighted a significant disruption to autophagy, with a dramatic increase in autophagosomes. A whole genome CRISPR-Cas9 screen identified the lysosomal V-ATPase as a key mediator of cell sensitivity to Compound X. This was further demonstrated by a rescue of toxicity Discussion: This mechanism is a further demonstration of how the physicochemical properties of bifunctional degraders may challenge preclinical development, and its elucidation provides a path forward for development of degrader compounds with improved toxicity profiles.
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