2. Academic Validation
  3. The novel tertiary amine LSD1 inhibitor 596 inhibits endometrial cancer through the mTOR signal transduction pathway

The novel tertiary amine LSD1 inhibitor 596 inhibits endometrial cancer through the mTOR signal transduction pathway

  • Transl Oncol. 2026 Apr:66:102688. doi: 10.1016/j.tranon.2026.102688.
Chunli Wang 1,  Dandan Shen 1,  Nanshan Lin 2,  Panjie Wang 3,  Yaping Bi 4,  Huina Hu 3,  Yujia Shang 3,  Chenchen Ren 5,  Li Yang 6,  Qisheng Ma 7
Affiliations

Affiliations

  • 1 Department of gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China) /Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, 450000, China; National Clinical Research Center for Obstetrics and Gynecology, Henan Branch, Zhengzhou 450052; Zhengzhou Key Laboratory of Cervical Diseases, Zhengzhou 450052.
  • 2 The Second Clinical Medical College, Zhengzhou University, Zhengzhou 450000, Henan, China.
  • 3 Department of gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China) /Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, 450000, China.
  • 4 Department of Pharmacology, School of Basic Medicine, Zhengzhou University, 100 Kexue Road, Zhengzhou, Henan, 450000, China.
  • 5 Department of gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China) /Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, 450000, China; National Clinical Research Center for Obstetrics and Gynecology, Henan Branch, Zhengzhou 450052; Zhengzhou Key Laboratory of Cervical Diseases, Zhengzhou 450052. Electronic address: [email protected].
  • 6 Department of gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China) /Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, 450000, China; National Clinical Research Center for Obstetrics and Gynecology, Henan Branch, Zhengzhou 450052; Zhengzhou Key Laboratory of Cervical Diseases, Zhengzhou 450052. Electronic address: [email protected].
  • 7 Department of Pathology, Bengbu Medical College, Bengbu, Anhui 233030, China. Electronic address: [email protected].
PMID: 41671780 DOI: 10.1016/j.tranon.2026.102688
Abstract

Lysine-specific demethylase 1 (LSD1) is a promising target in Cancer therapy and plays an important role in the occurrence and development of tumors. However, research on LSD1 in endometrial Cancer (EC) is indeed limited, and the related research on LSD1 inhibitors targeting EC is even rarer. In this study, our group developed a novel Tertiary Amine LSD1 inhibitor-596. 596 could specifically target LSD1 and inhibit the demethylation levels of H3K4me1/2 in a dose-dependent manner, thereby inhibited the proliferation of EC cells in vitro and in vivo. Moreover, in-depth studies have shown that 596 induces cell death in EC cells through the Autophagy pathway, increasing the formation of autophagosomes and the expression of autophagy-related proteins. Transcriptomic Sequencing revealed that 596-induced gene enrichment was related to the PI3K/Akt/mTOR pathway. The treatment group of 596 was able to attenuate the activation of the mTOR signaling cascade, and the combination treatment of 596 and the mTOR Inhibitor rapamycin (RAPA) effectively reduced the survival rate, migration ability, and invasion ability of EC cells. Further studies in vitro and in vivo indicated that 596 could reduce the feedback activation of Akt mediated by the mTOR Inhibitor rapamycin. In summary, our findings demonstrate that the LSD1 inhibitor 596 enhances the activity of the mTOR Inhibitor by attenuating the feedback activation of Akt. LSD1 may be as a potential therapeutic target in EC, and LSD1 inhibitors represent an important therapeutic strategy in EC treatment.

Keywords

596; Autophagy; Endometrial cancer; LSD1 inhibitor; Rapamycin; mTOR.

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