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Scientists Find a New Strategy for the Kidney Cancer Therapy
Update time: 2016-09-13
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Scientists from Shanghai Institute of Materia Medica (SIMM) CAS, along with collaborators from Beijing Institute of Genomics (BIG) CAS, have identified a novel small-molecule inhibitor of E3 ligase adaptor SPOP (Speckle-type POZ protein) that can disrupt the SPOP-substrate protein-protein interaction, providing an alternative approach specifically for the treatment of kidney cancer. This finding was published in the prestige journal Cancer cell on September 12, 2016.  

Dysregulation of ubiquitin signaling is significantly associated with multiple tumorigenesis. SPOP is an adaptor that bridges E3 ubiquitin ligase and the substrate proteins. The previous study demonstrated that SPOP, in 99% of clear cell Renal Cell Carcinoma (ccRCC), is overexpressed and dislocated in the cytoplasm, leading to kidney tumorigenesis. However, E3 ligase adaptor SPOP could be a classically “undruggable” target in terms of protein-protein interaction; therefore, inhibitors targeting SPOP have not been identified. 

Through a structure-based computational design and synthetic optimization, the team from SIMM and BIG has identified the lead compound 6b that can bind to SPOP and disrupt the SPOP-substrate protein interactions. In addition, the researchers find that compound 6b can successfully prevent ubiquitination and degradation of the oncogenic substrates of SPOP in cells, and it also can inhibit the proliferation of the primary human ccRCC cells isolated from seven patients and reduce the growth of ccRCC xenograft in nude mice. The cellular target engagement of compound 6b was carefully investigated by using genetic methods and the thermal shift assays. Of note, this inhibitor minimally affects the viability of normal kidney cells and other cancer cells in which SPOP is not accumulated in the cytoplasm. These results have demonstrated that compound 6b targeting SPOP-substrates interactions might be specific to kidney cancer. 

RCC, which accounts for about 4% of all cancers, is notorious for the resistance to radiotherapy and chemotherapy. The previous study revealed that ccRCC accounts for up to 75% of all kidney cancers. The kinase inhibitors, such as sorafenib and sunitinib are the major options for the treatment of metastatic ccRCC however, the complete response to these drugs is inefficient and kidney cancer patients quickly show drug resistance. Therefore, there are urgent needs to develop novel small-molecule inhibitors that effect on the new targets for kidney cancer therapy. And this study indicates that the small-molecule inhibitors of SPOP might be a specific approach alternative to the kinase inhibitors for the targeted therapy of ccRCC. 

The work is quite unique requiring diverse expertise across three different groups. Professors JIANG Hualiang’s and YANG Cai-Guang’s laboratories in SIMM, as well as professor LIU Jiang’s laboratory in BIG are heavily involved and work together to move the research forward. In addition, this work is jointly supported by researchers from Peking University First Hospital, Zhongnan Hospital of Wuhan University, University of Chinese Academy of Science, and Lanzhou University. The project partially sponsored by the National Key Research and Development Projects, the National Natural Science Foundation of China and the Youth Innovation Promotion Association of CAS. 

  

Small-molecule targeting of E3 ligase adaptor SPOP in kidney cancer

(image by SIMM and BIG)

 

Full text link: http://www.cell.com/cancer-cell/fulltext/S1535-6108(16)30386-5

 

 
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