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A Small Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

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A Small Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression Author Manuscript Published OnlineFirst on November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 1 A Small Molecule Inhibitor Targeting TRIP13 suppresses 2 multiple myeloma progression 3 Yingcong Wang,1,* Jing Huang, 2,* Bo Li,3,* Han Xue,2,* Guido Tricot,4 , Liangning Hu,1 4 Zhijian Xu,3 Xiaoxiang Sun,5 Shuaikang Chang,1 Lu Gao,1 Yi Tao,1 Hongwei Xu,4 5 Yongsheng Xie,1 Wenqin Xiao,1 Dandan Yu,1 Yuanyuan Kong,1 Gege Chen,1 Xi Sun,1 6 Fulin Lian,3 Naixia Zhang,3 Xiaosong Wu,1 Zhiyong Mao,5 Fenghuang Zhan,4 Weiliang 7 Zhu,3, † and Jumei Shi1,6, † 8 1Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University 9 School of Medicine, Shanghai 200072, China 10 2Shanghai Institute of Precision Medicine, The Ninth People’s Hospital, Shanghai Jiao 11 Tong University School of Medicine, Shanghai 200011, China 12 3CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, 13 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and University 14 of Chinese Academy of Sciences, Shanghai 201203, China 15 4Department of Internal Medicine, University of Iowa Carver College of Medicine, 16 Iowa City, IA, USA 17 5Clinical and Translational Research Center of Shanghai First Maternity & Infant 18 Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of 19 Life Sciences and Technology, Tongji University, Shanghai 200092, China 20 6Tongji University Cancer Center, Tongji University, Shanghai 200092, China 21 *Co-first author. 22 †Correspondence Authors: Jumei Shi, MD & PhD. Department of Hematology 23 Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 24 Yanchang Road, Shanghai 200072, China, Phone: +86-021-66306764, 25 [email protected], Weiliang Zhu, PhD. Drug Discovery and Design Center, 26 Shanghai Institute of Materia Medica, 555 Zuchongzhi Road, Shanghai 201203, China, 27 Phone: +86-021-50806600,[email protected] 28 1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 29 Running Title: A TRIP13 Inhibitor Suppresses Multiple myeloma Progression 30 Key words: TRIP13, Inhibitor, Multiple myeloma 31 Conflict of Interest: The authors declare that there is no conflict of interests. 32 Word count: 5422 33 Number of figures and tables: 7 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 2 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 49 Abstract 50 The AAA-ATPase TRIP13 drives multiple myeloma (MM) progression. Here we 51 present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A 52 small molecule inhibitor targeting TRIP13 was identified based on the crystal structure. 53 The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, 54 nuclear magnetic resonance spectroscopy, and surface plasmon resonance binding 55 assays. DCZ0415 induced anti-myeloma activity in vitro, in vivo, and in primary cells 56 derived from drug-resistant myeloma patients. The inhibitor impaired nonhomologous 57 end joining repair and inhibited NF-κB activity. Moreover, combining DCZ0415 with 58 the MM chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced 59 synergistic anti-myeloma activity. Therefore, targeting TRIP13 may be an effective 60 therapeutic strategy for MM, particularly refractory or relapsed MM. 61 Significance 62 Findings identify TRIP13 as a potentially new therapeutic target in multiple myeloma. 63 Introduction 64 MM is characterized by clonal proliferation of malignant monoclonal plasma cells in 65 the bone marrow (1). Genomic instability, defined by a higher rate of acquisition of 66 genomic changes per cell division compared with normal cells, is a prominent feature 67 of MM cells. Approximately 86,000 new MM patients are diagnosed worldwide each 68 year (2). Although the prognosis of MM patients has improved with the increased use 69 of autologous stem cell transplantation and combinations of approved anti-myeloma 70 agents such as proteasome inhibitors (bortezomib, carfilzomib), immunomodulatory 71 drugs (lenalidomide, pomalidomide) and monoclonal antibodies (daratumumab, 72 elotuzumab), 5-year overall survival rate is only 45% (3). Genetic complexity and 73 clonal heterogeneity are the main reasons for cancer treatment failure in MM patients 74 (4). Thus, the identification of a key driver gene for MM may enable the specific 75 targeting of these malignant cells. 3 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 76 Accumulating evidence has shown that dysregulated thyroid hormone 77 receptor-interacting protein 13 (TRIP13) protein levels are operational in several 78 tumors, including breast, liver, gastric, lung, prostate cancer, human chronic 79 lymphocytic leukemia, and Wilms’ tumor (5,6). TRIP13 is the mouse ortholog of 80 pachytene checkpoint 2 (Pch2) (7). During mitosis, TRIP13 regulates the spindle 81 assembly checkpoint via remodeling of its effector MAD2 from a ‘closed’ (active) into 82 an ‘open’ (inactive) form (8). During meiosis, TRIP13 was found to regulate meiotic 83 recombination in Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila 84 (9). A recent study indicated that TRIP13 enhanced NHEJ repair and induced treatment 85 resistance via binding to NHEJ proteins KU70/KU80/DNA-PKcs in head and neck 86 cancer (10). 87 In our previous study, TRIP13 was identified as a chromosome instability gene 88 that was correlated with MM drug resistance, disease relapse and poor outcomes in 89 MM patients (11). TRIP13 was first identified by yeast two-hybrid screening as a 90 protein fragment that was associated with thyroid hormone receptor in a 91 hormone-independent fashion (12). Overexpressing TRIP13 in cancer cells prompted 92 cell growth and drug resistance, while targeting TRIP13 by TRIP13 shRNA inhibited 93 MM cell growth, induced cell apoptosis and reduced the tumor burden in xenograft 94 MM mice (11). Our previous results suggested that TRIP13 might serve as a biomarker 95 for MM disease development and prognosis, making it a potential target for future 96 therapies. 97 To identify a TRIP13 inhibitor, detailed structural information of TRIP13 is 98 essential. Although the reported crystal structure of the TRIP13 mutant (E253Q or 99 E253A) provided insight into the mechanism of substrate recognition (8), further 100 structural information of the wild-type TRIP13 protein is needed for specific inhibitor 101 development. In this study, we determined the crystal structure of the wild-type human 102 TRIP13 at a resolution of 2.6 Å. We then identified small molecular inhibitors of 103 TRIP13 based on its crystal structure via molecular docking and bioassay. A small 104 molecular inhibitor, designated DCZ0415, was confirmed to bind to TRIP13 by 105 pull-down, NMR spectroscopy, SPR assays. DCZ0415 exhibited significant 4 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 15, 2019; DOI: 10.1158/0008-5472.CAN-18-3987 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 106 anti-myeloma activity in vitro, in vivo and in patient MM cells. Importantly, DCZ0415 107 also synergized with melphalan and the histone deacetylase (HDAC) inhibitor 108 panobinostat in MM cells. 109 Materials and Methods 110 Cell lines and patient samples 111 U266, HEK293T, MOPC-315 and HS-5 cells were commercially obtained from the 112 American Type Culture Collection (ATCC) (Mananssas, VA, USA). ARP-1, 113 OCI-MY5, RPMI-8226, and H929 cells were provided by Dr. Fenghuang Zhan 114 (University of Iowa, Iowa City, IA, USA). Cell lines were certificated by STR analysis 115 (Shanghai Biotechnology Co., Ltd., Shanghai, China). Mycoplasma testing was 116 performed using MycoAlert Mycoplasma Detection Kit (Basel, Switzerland) according 117 to the manufacturer’s recommended protocols. MM cells were maintained in RPMI 118 1640 medium (Gibco, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum 119 (FBS; Gibco, BRL, USA) and 1% penicillin-streptomycin (PS; Gibco, Carlsbad, CA, 120 USA). Human HS-5, HEK293T and mouse MOPC-315 cells were maintained in 121 Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Carlsbad, CA, USA) 122 supplemented with 10% FBS and 1% penicillin-streptomycin. All cells were 123 maintained in a humidified atmosphere of 5% CO2 at 37 °C, subcultured every 3 days 124 and passaged routinely for use until passage 20. Bone marrow samples were obtained 125 from MM patients after obtaining written informed consent at the Department of 126 Hematology Shanghai Tenth People’s Hospital (Shanghai, China). The protocol for 127 collection and usage of clinical samples
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