A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

Yingcong Wang; Jing Huang; Bo Li; Han Xue; Guido Tricot; Liangning Hu; Zhijian Xu; Xiaoxiang Sun; Shuaikang Chang; Lu Gao; Yi Tao; Hongwei Xu; Yongsheng Xie; Wenqin Xiao; Dandan Yu; Yuanyuan Kong; Gege Chen; Xi Sun; Fulin Lian; Naixia Zhang; Xiaosong Wu; Zhiyong Mao; Fenghuang Zhan; Weiliang Zhu; Jumei Shi

doi:10.1158/0008-5472.CAN-18-3987

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. Epub 2019 Nov 15.

Authors

Yingcong Wang^#¹, Jing Huang^#², Bo Li^#³, Han Xue^#², 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 Zhu⁶, Jumei Shi^{7

8}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors*
ATPases Associated with Diverse Cellular Activities / chemistry
ATPases Associated with Diverse Cellular Activities / metabolism
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / metabolism
Cell Proliferation
Crystallography, X-Ray
Disease Progression
Enzyme Inhibitors / pharmacology*
Humans
Melphalan / administration & dosage
Mice
Mice, Inbred BALB C
Mice, Nude
Multiple Myeloma / drug therapy*
Multiple Myeloma / metabolism
Multiple Myeloma / pathology
Panobinostat / administration & dosage
Protein Conformation
Pyridines / pharmacology*
Small Molecule Libraries / pharmacology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Cell Cycle Proteins
Enzyme Inhibitors
Pyridines
Small Molecule Libraries
Panobinostat
ATPases Associated with Diverse Cellular Activities
TRIP13 protein, human
Melphalan