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

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 in a KYSE-150 xenograft tumor model without
obvious signs of toxicity, while LI-1 is largely ineffective. Collectively,
LD-110 is a promising therapeutic candidate for PROTAC-based targeted
therapy of ESCC through LSD1 degradation and can also be used as a
versatile tool for probing LSD1 biology.