Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments.

ABSTRACT: Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure-activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacok

SUBMITTER: Kouridaki ME 

PROVIDER: S-EPMC11956012 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature