2. Academic Validation
  3. TI17, a novel compound, exerts anti-MM activity by impairing Trip13 function of DSBs repair and enhancing DNA damage

TI17, a novel compound, exerts anti-MM activity by impairing Trip13 function of DSBs repair and enhancing DNA damage

  • Cancer Med. 2023 Nov 9. doi: 10.1002/cam4.6706.
Shuaikang Chang 1,  Wenqin Xiao 2,  Yongsheng Xie 3,  Zhijian Xu 4,  Bo Li 4,  Guanli Wang 1,  Ke Hu 1,  Yong Zhang 4,  Jinfeng Zhou 3,  Dongliang Song 3,  Huabin Zhu 3,  Xiaosong Wu 3,  Yumeng Lu 3,  Jumei Shi 1,  Weiliang Zhu 4
Affiliations

Affiliations

  • 1 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
PMID: 37942576 DOI: 10.1002/cam4.6706
Abstract

Background: Thyroid Hormone Receptor interacting protein 13 (Trip13) is an AAA-ATPase that regulates the assembly or disassembly protein complexes and mediates Double-strand breaks (DSBs) repair. Overexpression of Trip13 has been detected in many cancers and is associated with myeloma progression, disease relapse and poor prognosis inmultiple myeloma (MM).

Methods: We have identified a small molecular, TI17, through a parallel compound-centric approach, which specifically targets Trip13. To identify whether TI17 targeted Trip13, pull-down and nuclear magnetic resonance spectroscopy (NMR) assays were performed. Cell counting kit-8, clone formation, Apoptosis and cell cycle assays were applied to investigate the effects of TI17. We also utilized a mouse model to investigate the effects of TI17 in vivo.

Results: TI17 effectively inhibited the proliferation of MM cells, and induced the cycle arrest and Apoptosis of MM cells. Furthermore, treatment with TI17 abrogates tumor growth and has no apparent side effects in mouse xenograft models. TI17 specifically impaired Trip13 function of DSBs repair and enhanced DNA damage responses in MM. Combining with melphalan or HDAC Inhibitor panobinostat triggers synergistic anti-MM effect.

Conclusions: Our study suggests that TI17 could be acted as a specific inhibitor of Trip13 and supports a preclinical proof of concept for therapeutic targeting of Trip13 in MM.

Keywords

DNA damage; DSBs repair; TI17; Trip13; myeloma.

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