Bunu Samuel Jacob, Cai Haiyan, Zhou Zhaoyin, Zhang Yanlei, Lai Yue, Wang Guanli, Song Dongliang, Wu Chengkun, Zheng Hang, Xu Zhijian, Shi Jumei, Zhu Weiliang
State Key Laboratory of Drug Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 China.
School of Pharmacy, University of Chinese Academy of Sciences No. 19A Yuquan Road Beijing 100049 China.
RSC Med Chem. 2025 May 6. doi: 10.1039/d4md01008f.
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 IC = 5.25 μM (NCI-H929 cell line), comparable with the positive control DCZ0415 (IC = 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.
甲状腺激素受体相互作用蛋白13（TRIP13）是一种AAA型ATP酶，可调节蛋白质复合物的组装和解聚，已知是一种具有修复DNA双链断裂能力的染色体不稳定基因。TRIP13的过表达与包括多发性骨髓瘤（MM）在内的许多人类恶性肿瘤的增殖和发展有关。因此，TRIP13被认为是抗癌药物开发的潜在药物靶点。虽然已经报道了一些TRIP13抑制剂，但目前尚无处于临床试验阶段或获批临床使用的药物。本研究旨在通过分子建模和生物测定，鉴定出结构不同于先前报道化合物的新型小分子作为潜在的TRIP13抑制剂。结果，成功鉴定出5种化合物为新型TRIP13抑制剂。F368-0183表现出最佳的抗增殖活性，IC50 = 5.25 μM（NCI-H929细胞系），与阳性对照DCZ0415（IC50 = 9.64 μM）相当。此外，细胞热迁移分析证实该化合物可与MM细胞中的TRIP13蛋白相互作用。另外，AAA型ATP酶抑制生物测定表明，这5种化合物的抑制活性优于DCZ0415，与计算得到的自由能微扰（FEP）具有强相关性。进一步的分子动力学模拟研究表明，这些新型化合物可与TRIP13的12个残基显著相互作用，尤其是R386、L139、R389、L135、S138、Y141和G385。我们还评估了F368-0183对激酶组的抑制作用，未发现其他靶点，但不能完全排除这些化合物与其他靶蛋白潜在结合的可能性。因此，这些化合物的新分子骨架、它们在抑制MM细胞系增殖方面的功效以及所显示的TRIP13 AAA型ATP酶抑制特性，为开发新型基于TRIP13的多靶点抗MM药物提供了重要线索。
