LD-110, a potent LSD1 PROTAC degrader, suppresses tumor growth by inducing ER stress and apoptosis

Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is frequently overexpressed in multiple cancer types and associated with poor prognosis of cancer patients. While LSD1 represents a compelling therapeutic target, clinical development of small-molecule inhibitors has been hampered by dose-limiting toxicities and off-target effects. In this study, we reported the discovery of LD-110 as a potent proteolysis targeting chimera (PROTAC) specifically engineered for LSD1 degradation. LD-110 effectively degrades LSD1 via the ubiquitin-proteasome system and significantly suppresses the growth and survival of breast and lung cancer cells. Mechanistically, LD-110 triggers endoplasmic reticulum stress by activating the ATF4-CHOP signal to increase NOXA levels, but decrease MCL1 levels, along with increasing ROS production and prolonged DNA damage to trigger phosphorylation of GCN2 and eIF2α for enhanced ATF4 translation, ultimately inducing apoptotic cell death. Importantly, LD-110 demonstrated a good in vivo pharmacokinetic profile and effectively inhibited in vivo tumor growth in breast and lung xenograft tumor models. Collectively, we discovered a potent PROTAC degrader targeting LSD1 with effective anti-cancer activity for future development as a promising anti-cancer agent.