Off-target autophagy disruption associated with a novel liver toxicity in dogs for a highly basic heterobifunctional protein degrader.

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 in vitro recapitulation. Cholangiocytes, epithelial cells lining bile ducts, were the toxicity target, with an accumulation of Compound X in both bile and the affected cells.

Results

Proteome profiling and high-content imaging highlighted a significant disruption to autophagy,

SUBMITTER: Kath JE 

PROVIDER: S-EPMC12727973 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature