2. Academic Validation
  3. Potent and selective LSD1 inhibitor DC551040 reveals a promising combination therapy for AML with insight into epigenetic dysregulation

Potent and selective LSD1 inhibitor DC551040 reveals a promising combination therapy for AML with insight into epigenetic dysregulation

  • Signal Transduct Target Ther. 2026 Mar 23;11(1):108. doi: 10.1038/s41392-026-02637-0.
Jiang Wang # 1 2 3,  Hanlin Wang # 4 5 6,  Runhua Du # 3 4 5,  Chunpu Li # 1 3 7,  Mingbo Su 4,  Shuni Wang 1,  Weijuan Kan 4,  Guobin Liu 3 4,  Yu Zhang 1 2,  Xiaobei Hu 4 8,  Feng Gao 1,  Gaoya Xu 4,  Cong Li 4,  Wei Zhu 1,  Yunfei Ye 4,  Li Sheng 4,  Yuqiang Shi 1,  Yingying Shao 4,  Jiangzhou Song 4,  Yuxian Wang 4,  Bo Wang 4,  Yubo Zhou 9,  He Huang 10 11 12 13,  Jia Li 14 15 16 17 18 19 20,  Hong Liu 21 22 23 24
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 Lingang Laboratory, Shanghai, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 University of Chinese Academy of Sciences, Beijing, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China.
  • 7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 8 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 9 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China. [email protected].
  • 10 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 11 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 12 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 13 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China. [email protected].
  • 14 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 15 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 16 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 17 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China. [email protected].
  • 18 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  • 19 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 20 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China. [email protected].
  • 21 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 22 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 23 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China. [email protected].
  • 24 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 41872160 DOI: 10.1038/s41392-026-02637-0
Abstract

Epigenetic dysregulation is a fundamental Cancer hallmark, and lysine demethylase 1 (LSD1) is a central target for Cancer intervention. Developing novel LSD1 inhibitors with high selectivity, favorable bioavailability, and safety for acute myeloid leukemia (AML) remains challenging. We developed DC551040, a highly potent, selective irreversible LSD1 inhibitor with good tolerability in Phase I AML clinical trial (CTR20222026). DC551040-LSD1 complex crystal structure uncovered a new binding pocket, providing molecular insights for subsequent LSD1 inhibitor design. Given the significant role of LSD1 in epigenetic regulation, we performed comprehensive transcriptomic and proteomic analyses to investigate gene and protein expression dynamics following DC551040 treatment in an MV-4-11 xenograft model. These analyses revealed that multiple immune and inflammation related pathways are activated upon DC551040 treatment, including the key members STAT5, NF-κB, and Akt, suggesting the potential for adaptive resistance. Through a search of the Connectivity Map (CMAP) database, we identify homoharringtonine (HHT), an approved anti-leukemia drug, which mimics the anti-transcriptional activation of inflammatory pathways. Subsequent in vitro and in vivo experiments validated the efficacy of combining HHT with DC551040, demonstrating a synergistic antitumor effect and extended survival in MV-4-11 disseminated xenograft model mice. Together, this study not only introduces a novel LSD1 inhibitor but also delves into the molecular mechanisms underlying LSD1 inhibitors, while proposing a promising combination therapy for AML individuals in clinical trials.

Figures
Products
Inhibitors & Agonists
Other Products