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Updated: Jul 11, 2025
Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
Published on: September 28, 2012
TI17, a novel compound, exerts anti-MM activity by impairing Trip13 function of DSBs repair and enhancing DNA damage
Shuaikang Chang1, Wenqin Xiao2, Yongsheng Xie3
1Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
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.
Insights
A new compound, TI17, specifically targets Thyroid hormone receptor interacting protein 13 (Trip13), inhibiting multiple myeloma (MM) cell growth and tumor progression. This preclinical study supports TI17 as a potential therapeutic for MM by impairing DNA repair mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Thyroid hormone receptor interacting protein 13 (Trip13) is an AAA-ATPase involved in protein complex regulation and DNA repair.
- Trip13 overexpression is linked to multiple myeloma (MM) progression, relapse, and poor prognosis.
Purpose of the Study:
- To identify and characterize a small molecule inhibitor targeting Trip13.
- To evaluate the therapeutic potential of the identified inhibitor in multiple myeloma.
Main Methods:
- Compound-centric screening identified TI17 as a Trip13 inhibitor.
- In vitro assays (proliferation, apoptosis, cell cycle) and in vivo mouse xenograft models were used.
- Mechanism of action explored via DNA damage response and repair assays.
Main Results:
- TI17 inhibited MM cell proliferation, induced cell cycle arrest, and promoted apoptosis.
- TI17 abrogated tumor growth in vivo with no apparent side effects.
- TI17 impaired Trip13's role in DNA double-strand break (DSB) repair and enhanced DNA damage responses.
- Synergistic anti-MM effects were observed when TI17 was combined with melphalan or panobinostat.
Conclusions:
- TI17 acts as a specific Trip13 inhibitor.
- This study provides preclinical proof of concept for targeting Trip13 in MM therapy.
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