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A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Published OnlineFirst November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 CANCER RESEARCH | TRANSLATIONAL SCIENCE A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression Yingcong Wang1, Jing Huang2,BoLi3, Han Xue2, Guido Tricot4, Liangning Hu1, Zhijian Xu3, Xiaoxiang Sun5, Shuaikang Chang1, Lu Gao1, Yi Tao1, Hongwei Xu4, Yongsheng Xie1, Wenqin Xiao1, Dandan Yu1, Yuanyuan Kong1, Gege Chen1, Xi Sun1, Fulin Lian3, Naixia Zhang3, Xiaosong Wu1, Zhiyong Mao5, Fenghuang Zhan4, Weiliang Zhu3, and Jumei Shi1,6 ABSTRACT ◥ The AAA-ATPase TRIP13 drives multiple myeloma progres- The inhibitor impaired nonhomologous end joining repair and sion. Here, we present the crystal structure of wild-type human inhibited NF-kB activity. Moreover, combining DCZ0415 with TRIP13 at a resolution of 2.6 Å. A small-molecule inhibitor the multiple myeloma chemotherapeutic melphalan or the targeting TRIP13 was identified on the basis of the crystal HDAC inhibitor panobinostat induced synergistic antimyeloma structure. The inhibitor, designated DCZ0415, was confirmed activity. Therefore, targeting TRIP13 may be an effective ther- to bind TRIP13 using pull-down, nuclear magnetic resonance apeutic strategy for multiple myeloma, particularly refractory or spectroscopy, and surface plasmon resonance–binding assays. relapsed multiple myeloma. DCZ0415 induced antimyeloma activity in vitro, in vivo,andin Significance: These findings identify TRIP13 as a potentially primary cells derived from drug-resistant patients with myeloma. new therapeutic target in multiple myeloma. Introduction plexity and clonal heterogeneity are the main reasons for cancer treatment failure in patients with multiple myeloma (4). Thus, the Multiple myeloma is characterized by clonal proliferation of malig- identification of a key driver gene for multiple myeloma may enable the nant monoclonal plasma cells in the bone marrow (1). Genomic specific targeting of these malignant cells. instability, defined by a higher rate of acquisition of genomic changes Accumulating evidence has shown that dysregulated thyroid per cell division compared with normal cells, is a prominent feature of hormone receptor–interacting protein 13 (TRIP13) protein levels multiple myeloma cells. Approximately 86,000 new patients with are operational in several tumors, including breast, liver, gastric, multiple myeloma are diagnosed worldwide each year (2). Although lung, prostate cancer, human chronic lymphocytic leukemia, and the prognosis of patients with multiple myeloma has improved with Wilmstumor(5,6).TRIP13isthemouse ortholog of pachytene the increased use of autologous stem cell transplantation and combi- checkpoint 2 (7). During mitosis, TRIP13 regulates the spindle nations of approved antimyeloma agents such as proteasome inhibi- assembly checkpoint via remodeling of its effector MAD2 from a tors (bortezomib and carfilzomib), immunomodulatory drugs (lena- “closed” (active) into an “open” (inactive) form (8). During meiosis, lidomide and pomalidomide), and mAbs (daratumumab and elotu- TRIP13 was found to regulate meiotic recombination in Saccharo- zumab), 5-year overall survival rate is only 45% (3). Genetic com- myces cerevisiae, Caenorhabditis elegans,andDrosophila (9). A recent study indicated that TRIP13 enhanced nonhomologous end joining (NHEJ) repair and induced treatment resistance via binding 1 Department of Hematology, Shanghai Tenth People's Hospital, Tongji Univer- to NHEJ proteins KU70/KU80/DNA-PKcs in head and neck sity School of Medicine, Shanghai, China. 2Shanghai Institute of Precision cancer (10). Medicine, The Ninth People's Hospital, Shanghai Jiao Tong University School fi of Medicine, Shanghai, China. 3CAS Key Laboratory of Receptor Research, Drug In our previous study, TRIP13 was identi ed as a chromosome Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese instability gene that was correlated with multiple myeloma drug Academy of Sciences, and University of Chinese Academy of Sciences, Shanghai, resistance, disease relapse, and poor outcomes in patients with mul- China. 4Department of Internal Medicine, University of Iowa Carver College of tiple myeloma (11). TRIP13 was first identified by yeast two-hybrid 5 Medicine, Iowa City, Iowa. Clinical and Translational Research Center of Shang- screening as a protein fragment that was associated with thyroid hai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and hormone receptor in a hormone-independent fashion (12). Over- Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. 6Tongji University Cancer Center, Tongji University, Shanghai, expressing TRIP13 in cancer cells prompted cell growth and drug China. resistance, while targeting TRIP13 by TRIP13 shRNA inhibited mul- Note: Supplementary data for this article are available at Cancer Research tiple myeloma cell growth, induced cell apoptosis, and reduced the Online (http://cancerres.aacrjournals.org/). tumor burden in xenograft multiple myeloma mice (11). Our previous results suggested that TRIP13 might serve as a biomarker for multiple Y. Wang, J. Huang, B. Li, and H. Xue are the co-first authors of this article. myeloma disease development and prognosis, making it a potential Corresponding Authors: Jumei Shi, Shanghai Tenth People's Hospital, Tongji target for future therapies. University School of Medicine, 301 Yanchang Road, Shanghai 200072, China. To identify a TRIP13 inhibitor, detailed structural information of Phone: 8618-9176-83490; Fax: 8621-6630-6641; E-mail: [email protected]; and Weiliang Zhu, [email protected] TRIP13 is essential. Although the reported crystal structure of the TRIP13 mutant (E253Q or E253A) provided insight into the mech- Cancer Res 2020;80:536–48 anism of substrate recognition (8), further structural information doi: 10.1158/0008-5472.CAN-18-3987 of the wild-type TRIP13 protein is needed for specific inhibitor Ó2019 American Association for Cancer Research. development. In this study, we determined the crystal structure of AACRJournals.org | 536 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 A TRIP13 Inhibitor Suppresses Multiple Myeloma Progression the wild-type human TRIP13 at a resolution of 2.6 Å. We then were performed at 25C with Biacore T2000 (GE Healthcare). In this identified small-molecule inhibitors of TRIP13 based on its crystal step, compounds were diluted at different concentrations in PBS buffer structure via molecular docking and bioassay. A small-molecule (10 mmol/L HEPES pH ¼ 7.4, 150 mmol/L NaCl, 3 mmol/L EDTA), inhibitor, designated DCZ0415, was confirmed to bind to TRIP13 by and were flowed over the chip at rate of 30 mL/minute. The combining pull-down, nuclear magnetic resonance (NMR) spectroscopy, surface time and dissociation time was set at 120 and 150 seconds, respectively. plasmon resonance (SPR) assays. DCZ0415 exhibited significant Data analysis was finished via the state model of T2000 evaluation antimyeloma activity in vitro, in vivo, and in patient multiple myeloma software (GE Healthcare). cells. Importantly, DCZ0415 also synergized with melphalan and the histone deacetylase (HDAC) inhibitor panobinostat in multiple mye- Cell viability assay loma cells. Cell viability assay was performed as described previously (13). Briefly, cells were seeded in triplicate in 96-well plates and then treated with DCZ0415. Cell viability was measured using the Cell Counting Kit Materials and Methods (CCK)-8 assays. Cell lines and patient samples U266, HEK293T, MOPC-315, and HS-5 cells were commercially Apoptosis assay obtained from the ATCC. ARP-1, OCI-MY5, RPMI-8226, and H929 Apoptosis assay was performed as described previously (14). Briefly, cells were provided by Dr. Fenghuang Zhan (University of Iowa, Iowa cells were treated with or without DCZ0415. Then, cells were collected City, IA). Cell lines were certificated by short tandem repeat analysis and stained with Annexin-V for 15 minutes and then PI for 5 minutes (Shanghai Biotechnology Co., Ltd.). Mycoplasma testing was per- at room temperature. Stained cells were detected via using flow formed using MycoAlert Mycoplasma Detection Kit according to the cytometry. manufacturer's recommended protocols. Multiple myeloma cells were maintained in RPMI-1640 medium (Gibco) supplemented with 10% Crystallization, data collection, and structural determination FBS (Gibco) and 1% penicillin–streptomycin (Gibco). Human HS-5, Wild-type TRIP13 protein was mixed with AMP-PNP at a molar HEK293T and mouse MOPC-315 cells were maintained in DMEM ratio of 1:2 and incubated on ice for 1 hour to allow complex (Gibco) supplemented with 10% FBS and 1% penicillin–streptomycin. formation. Crystallization was achieved by sitting-drop vapor dif- fi All cells were maintained in a humidi ed atmosphere of 5% CO2 at fusion at 4 C with the well solution containing 0.1 mol/L bicine, 37C, subcultured every 3 days and passaged routinely for use until pH 9.0, and 10% (v/v) (Æ)-2-Methyl-2,4-pentanediol. Crystals passage 20. Bone marrow samples were obtained from patients with were gradually transferred to a harvesting solution containing multiple myeloma after obtaining written informed consent at the the precipitant solution and 25% glycerol, prior to flash-freezing Department of Hematology Shanghai Tenth People's Hospital (Shang- them in liquid nitrogen for storage. Native and Se-Met-SAD
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