2. Academic Validation
  3. A novel indirubin- 3-monoxime derivative I3MV- 8b exhibits remarkable cytotoxicity against multiple myeloma by targeting TRIM28

A novel indirubin- 3-monoxime derivative I3MV- 8b exhibits remarkable cytotoxicity against multiple myeloma by targeting TRIM28

  • Biomark Res. 2025 Apr 7;13(1):57. doi: 10.1186/s40364-025-00773-3.
Teng Fang # 1,  Lanting Liu # 1,  Hao Sun # 1,  Xiaoyu Zhang 1,  Xiyue Sun 1,  Zhen Yu 1,  Lixin Gong 1,  Shiyi Xie 1,  Yonglong Zhao 2,  Yan Li 2,  Lugui Qiu 1 3,  Gang An 1 3,  Bin He 4,  Mu Hao 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
  • 3 Department of Hospital Management, Gobroad Healthcare Group, Beijing, China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China. binhe@gmc.edu.cn.
  • 5 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. haomu@ihcams.ac.cn.
  • 6 Department of Hospital Management, Gobroad Healthcare Group, Beijing, China. haomu@ihcams.ac.cn.
  • # Contributed equally.
PMID: 40197552 DOI: 10.1186/s40364-025-00773-3
Abstract

Introduction: Maintaining protein homeostasis is vital for multiple myeloma (MM) cell survival. Indirubin- 3-monoxime (I3MO), a potential MM therapeutic, inhibits Proteasome activity, while histone deacetylase 6 (HDAC6) regulates Autophagy. We developed I3MV- 8b, an I3MO derivative, integrating an HDAC6 Inhibitor moiety to enhance dual inhibition of Proteasome and Autophagy pathways.

Methods: The anti-MM effects of I3MV- 8b were tested in vitro and in vivo. To identify downstream targets, RNA-seq and dual-luciferase reporter assays were performed. Additionally, ChIP-seq and IP-MS techniques were employed to elucidate the underlying molecular mechanism.

Results: I3MV- 8b significantly suppressed MM cell proliferation and induced Apoptosis. Combined with Proteasome inhibitors, I3MV- 8b enhanced cytotoxicity by concurrently inhibiting Proteasome and Autophagy pathways. It reduced TRIM28 transcription, correlating with lower expression of Proteasome subunits and autophagy-related genes. ChIP-seq revealed that TRIM28 binds to Proteasome gene promoters, and its knockdown decreased Proteasome subunit expression and activity. TRIM28 knockdown also impaired autophagosome formation. IP-MS and Co-IP assays showed TRIM28 interacted with 14-3 - 3ζ, a negative regulator of Autophagy, promoting its ubiquitination and degradation. This interaction reduced Autophagy regulation, further sensitizing cells to treatment.

Conclusions: I3MV- 8b offers a novel dual inhibition strategy targeting Proteasome and Autophagy, presenting a promising therapeutic option for MM.

Figures
Products