2. Academic Validation
  3. A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

  • Cancer Res. 2020 Feb 1;80(3):536-548. doi: 10.1158/0008-5472.CAN-18-3987.
Yingcong Wang  # 1,  Jing Huang  # 2,  Bo Li  # 3,  Han Xue  # 2,  Guido Tricot 4,  Liangning Hu 1,  Zhijian Xu 3,  Xiaoxiang Sun 5,  Shuaikang Chang 1,  Lu Gao 1,  Yi Tao 1,  Hongwei Xu 4,  Yongsheng Xie 1,  Wenqin Xiao 1,  Dandan Yu 1,  Yuanyuan Kong 1,  Gege Chen 1,  Xi Sun 1,  Fulin Lian 3,  Naixia Zhang 3,  Xiaosong Wu 1,  Zhiyong Mao 5,  Fenghuang Zhan 4,  Weiliang Zhu 6,  Jumei Shi 7 8
Affiliations

Affiliations

  • 1 Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Shanghai Institute of Precision Medicine, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and University of Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
  • 5 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 6 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and University of Chinese Academy of Sciences, Shanghai, China. [email protected] [email protected].
  • 7 Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. [email protected] [email protected].
  • 8 Tongji University Cancer Center, Tongji University, Shanghai, China.
  • # Contributed equally.
PMID: 31732653 DOI: 10.1158/0008-5472.CAN-18-3987
Abstract

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 Å. 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-κB 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.

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