Discovery of novel antimyeloma agents targeting TRIP13 by molecular modeling and bioassay
Samuel Jacob Bunu1,2,3, Haiyan Cai4, Zhaoyin Zhou1,5
1State Key Laboratory of Drug Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China.
Abstract:
Thyroid hormone receptor-interacting protein-13 (TRIP13) is an AAA+ ATPase that regulates protein complex assembly and disassembly and is known to be a chromosomal instability gene with the ability to repair DNA double-strand breaks. TRIP13 overexpression has been linked to the proliferation and development of many human malignancies, including multiple myeloma (MM). Accordingly, TRIP13 is recognized as a potential drug target for anticancer drug development. Although some TRIP13 inhibitors have been reported, none are under clinical trial or approved for clinical use. This study aimed to identify novel small molecules as potential TRIP13 inhibitors structurally different from previously reported compounds through molecular modeling and bioassays. As a result, five compounds were successfully identified as novel TRIP13 inhibitors. F368-0183 showed the best antiproliferative activity with IC50 = 5.25 μM (NCI-H929 cell line), comparable with the positive control DCZ0415 (IC50 = 9.64 μM). Also, the cellular thermal shift assay confirmed that this compound could interact with the TRIP13 protein in MM cells. In addition, the AAA+ ATPase inhibitory bioassay demonstrated that the five compounds had better inhibitory activity than DCZ0415, having strong correlations with the calculated free energy perturbation (FEP). Further molecular dynamics simulation studies revealed that the novel compounds could significantly interact with 12 residues of TRIP13, especially R386, L139, R389, L135, S138, Y141, and G385. We also assessed the F368-0183 inhibition on a kinase panel, no other targets were found, but the potential binding to other target proteins of these compounds cannot be totally excluded. Therefore, the new molecular scaffolds of these compounds, their efficacy in suppressing MM cell line proliferation, and the displayed TRIP13 AAA+ ATPase inhibitory properties provide important clues for developing novel TRIP13-based multi-target anti-MM drugs.
Insights
Researchers identified novel small molecules that inhibit TRIP13, a protein linked to multiple myeloma (MM). These compounds show promise for developing new anti-MM drugs targeting TRIP13's AAA+ ATPase activity.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Thyroid hormone receptor-interacting protein-13 (TRIP13) is an AAA+ ATPase involved in DNA repair and chromosomal stability.
- Overexpression of TRIP13 is associated with the proliferation of human malignancies, including multiple myeloma (MM).
- TRIP13 is a potential drug target, but no inhibitors are currently in clinical trials.
Purpose of the Study:
- To identify novel small molecules as potential TRIP13 inhibitors with unique structures.
- To evaluate the efficacy of these compounds in inhibiting TRIP13's AAA+ ATPase activity and suppressing MM cell proliferation.
Main Methods:
- Molecular modeling and in silico screening were employed to design and identify potential inhibitors.
- In vitro bioassays, including cellular thermal shift assay (CETSA) and AAA+ ATPase inhibition assays, were used for validation.
- Molecular dynamics simulations were performed to understand compound-protein interactions.
- A kinase panel assay assessed the selectivity of the identified inhibitors.
Main Results:
- Five novel TRIP13 inhibitors were identified, structurally distinct from existing compounds.
- Compound F368-0183 demonstrated significant antiproliferative activity against MM cell lines (IC50 = 5.25 μM).
- The identified compounds exhibited superior AAA+ ATPase inhibitory activity compared to the control, correlating with FEP calculations.
- Molecular dynamics simulations revealed specific interactions between the novel compounds and key TRIP13 residues.
Conclusions:
- Novel small molecules targeting TRIP13 have been discovered, showing potent antiproliferative effects on MM cells.
- These compounds represent promising scaffolds for developing new multi-target anti-MM drugs by inhibiting TRIP13's AAA+ ATPase activity.
- Further research is warranted to explore their therapeutic potential and optimize their structure for clinical application.
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