A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression
A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression
复制标题
靶向 TRIP13 的小分子抑制剂抑制多发性骨髓瘤进展
DOI：
10.1158/0008-5472.can-18-3987
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发表时间：
2020-02-01
期刊：
影响因子：
11.2
通讯作者：
Shi, Jumei
中科院分区：
文献类型：
--
作者：
Wang, Yingcong;Huang, Jing;Shi, Jumei
AAA-ATPase TRIP13驱动多发性骨髓瘤的进展。在这里，我们给出了野生型人TRIP13的晶体结构，分辨率为2.6A。根据晶体结构，我们鉴定了一种针对TRIP13的小分子抑制剂。该抑制剂命名为DCZ0415，通过下拉、核磁共振光谱和表面等离子体共振结合试验证实与TRIP13结合。DCZ0415在体外、体内和耐药骨髓瘤患者的原代细胞中诱导抗骨髓瘤活性。该抑制物损伤非同源末端连接修复并抑制核因子-kB的活性。此外，DCZ0415与多发性骨髓瘤化疗药物马法兰或HDAC抑制剂Panobinostat联合使用可诱导协同抗骨髓瘤活性。因此，靶向TRIP13可能是多发性骨髓瘤，特别是难治性或复发性多发性骨髓瘤的有效治疗策略。意义：这些发现确认TRIP13是治疗多发性骨髓瘤的潜在新靶点。
The AAA- ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 A. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays. DCZ0415 induced antimyeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant patients with myeloma. The inhibitor impaired nonhomologous end joining repair and inhibited NF-kB activity. Moreover, combining DCZ0415 with the multiple myeloma chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic antimyeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for multiple myeloma, particularly refractory or relapsed multiple myeloma.Significance: These findings identify TRIP13 as a potentially new therapeutic target in multiple myeloma.