Rational design and discovery of potent PROTAC degraders of ASK1: a targeted therapy in MASH.

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease marked by hepatic steatosis, inflammation, and fibrosis, with limited therapeutic options. This study introduces a novel PROTAC-based strategy for the selective degradation of apoptosis signal-regulating kinase 1 (ASK1), a key mediator of MASH pathology. We first developed dASK1 (35), a cereblon (CRBN)-based PROTAC, which successfully formed a stable ternary complex with ASK1, facilitating its rapid and sustained degradation via the ubiquitin-proteasome pathway. In vitro evaluations demonstrated potent ASK1 degradation in the 10-100 nM range (70% degradation at 100 nM) in HepG2 and HEK293A cell lines, validating the efficacy of dASK1 (35). To enhance the degradation mechanism

SUBMITTER: Sarkar HS 

PROVIDER: S-EPMC12150234 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature