Discovery of novel antimyeloma agents targeting TRIP13 by molecular modeling and bioassay

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.