Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Beijing Genomics Institute collaborate to confirm the new target for renal cancer treatment SPOP

Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Beijing Genomics Institute collaborate to confirm the new target for renal cancer treatment SPOP

September 20, 2016 Source: Medical Valley

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In recent years, the increase in the incidence of renal cancer ranks first in malignant tumors. Clinical treatment shows that kidney cancer is not sensitive to radiotherapy and chemotherapy. Targeted anti-tumor drugs represented by sorafenib and sunitinib are first-line treatments for advanced renal cell carcinoma, but the effect on metastatic renal cell carcinoma is very high. Limited and prone to resistance. Therefore, discovering and confirming the new target for the treatment of kidney cancer-specific drugs is a very urgent and significant task.

SPOP is a adaptor protein of the ubiquitin ligase E3 family member Cul3 binding substrate protein, which mediates the ubiquitination modification of many nuclear proteins, leading to protein degradation, thereby regulating various functions of cells. Dr. Liu Jiang of Beijing Genomics Institute found early that SPOP was overexpressed in 99% of clear cell renal cell carcinoma tissues, but was low in normal kidney tissues, and SPOP was still overexpressed in metastatic clear cell renal cell carcinoma, indicating SPOP It is a biomarker molecule for clear cell renal cell carcinoma (Science, 2009). Further research by Liu Jiang's research team found that SPOP was incorrectly located in the cytoplasm in clear cell renal cell carcinoma. Over-activated hypoxia-inducible factor HIF transcription enhances SPOP overexpression, and the hypoxic microenvironment drives large amounts of overexpressed SPOP protein in renal cancer cell mass, ultimately promoting renal cell carcinoma formation (CancerCell, 2014).

On September 12, 2016, CancerCell published a research paper entitled "Small-moleculetargeting of E3ligaseadaptor SPOP inkidneycancer" online. This is an important progress in the collaborative research between the Shanghai Institute of Medicine Jiang Hualiang, the Yang Caiguang Group and the Beijing Institute of Genomics Liu Jiang. In this study, SPOP interacts with protein as a target, and based on the characteristics of SPOP to recognize the crystal structure of the substrate polypeptide complex, a comprehensive application of structure-based virtual screening strategy, medicinal chemical synthesis optimization and other techniques to obtain small molecules capable of binding to SPOP. The compound, which inhibits the binding of SPOP to the substrate protein, interferes with SPOP-mediated signal transduction pathways that regulate the ubiquitination of PTEN, DUSP7 and other tumor suppressor proteins, and ultimately inhibits the growth of renal cancer cells in vitro and in vivo. This study demonstrated whether pharmacological function of SPOP can be used as a target for clear cell renal cancer drugs, and indicates a new direction different from kinase inhibitors for the discovery of SPOP inhibitors and for the treatment of renal cancer.

The research was completed by the Shanghai Institute of Materia Medica and the Beijing Genomics Institute. It was also supported by the First Hospital of Peking University, Zhongnan Hospital of Wuhan University, Beijing Normal University, and Lanzhou University. The research also received funding from the National Natural Science Foundation, the Ministry of Science and Technology, and the Chinese Academy of Sciences.

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