Discovery of LD-110 as an Effective LSD1 PROTAC Degrader for the Treatment of Esophagus Squamous Cancer.

ABSTRACT: LSD1, a pivotal epigenetic regulator mediating histone demethylation, is an attractive therapeutic target due to its oncogenic roles in cancers. Although numerous small-molecule inhibitors of LSD1 were advanced to clinical trials, only one PROTAC-based degrader was reported most recently. Here, we report a potent and efficacious proteolysis-targeting chimera (PROTAC) degrader, LSD1, designated as LD-110. Biochemically, LD-110 promotes LSD1 degradation and increases the level of H3K4 dimethylation in a ubiquitin-proteasome-dependent manner. Biologically, LD-110 inhibits the growth and survival of multiple esophagus squamous cancer cell (ESCC) lines by inducing apoptosis with much greater effectiveness than its small-molecule warhead LI-1. Finally, LD-110 effectively suppresses tumor growth

SUBMITTER: Zhuo J 

PROVIDER: S-EPMC12557393 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature