2. Academic Validation
  3. LD-110, a potent LSD1 PROTAC degrader, suppresses tumor growth by inducing ER stress and apoptosis

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

  • Sci Bull (Beijing). 2025 Dec 15;70(23):4046-4060. doi: 10.1016/j.scib.2025.10.024.
Danyi Zhai 1,  Jiezhen Zhuo 1,  Yudong Yin 1,  Lan Li 2,  Mengting Liang 2,  Xin Zhou 2,  Lihua Liu 1,  Liangzhen Chen 1,  Xiufang Xiong 1,  Qing Yu 3,  Xin Han 4,  Yi Sun 5
Affiliations

Affiliations

  • 1 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
  • 2 SunnyInnovation Co. Ltd, Hangzhou 310030, China.
  • 3 SunnyInnovation Co. Ltd, Hangzhou 310030, China. Electronic address: [email protected].
  • 4 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China. Electronic address: [email protected].
  • 5 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Cancer Center of Zhejiang University, Hangzhou 310009, China; Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou 310009, China; Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, China; State Key Laboratory of Transvascular Implantation Devices, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310029, China. Electronic address: [email protected].
PMID: 41188178 DOI: 10.1016/j.scib.2025.10.024
Abstract

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.

Keywords

Apoptosis; Cancer therapy; Endoplasmic reticulum stress; Histone H3K4 methylations; LSD1; PROTAC degrader.

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