Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

被引：79

作者：

Guo, Zhong-Qiang ^{[1
,3
,4
]}

Zheng, Tong ^{[2
,5
]}

Chen, Baoen ^{[2
]}

Luo, Cheng ^{[6
]}

Ouyang, Sisheng ^{[6
]}

Gong, Shouzhe ^{[2
]}

Li, Jiafei ^{[2
]}

Mao, Liu-Liang ^{[7
]}

Lian, Fulin ^{[8
]}

Yang, Yong ^{[9
]}

Huang, Yue ^{[2
,5
]}

Li, Li ^{[2
]}

Lu, Jing ^{[10
]}

Zhang, Bidong ^{[5
,6
]}

Zhou, Luming ^{[11
,12
]}

Ding, Hong ^{[6
]}

Gao, Zhiwei ^{[9
]}

Zhou, Liqun ^{[3
]}

Li, Guoqiang ^{[1
]}

Zhou, Ran ^{[6
]}

Chen, Ke ^{[1
]}

Liu, Jingqiu ^{[6
]}

Wen, Yi ^{[8
]}

Gong, Likun ^{[10
]}

Ke, Yuwen ^{[1
]}

Yang, Shang-Dong ^{[7
]}

Qiu, Xiao-Bo ^{[11
,12
]}

Zhang, Naixia ^{[8
]}

Ren, Jin ^{[10
]}

Zhong, Dafang ^{[9
]}

Yang, Cai-Guang ^{[2
]}

Liu, Jiang ^{[1
]}

Jiang, Hualiang ^{[6
]}

机构：

[1] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing 100101, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Biol Chem Lab, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[3] Peking Univ, Dept Urol, Hosp 1, Beijing 100034, Peoples R China

[4] Wuhan Univ, Dept Urol, Zhongnan Hosp, Wuhan 430071, Hubei, Peoples R China

[5] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[6] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[7] Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China

[8] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China

[9] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[10] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China

[11] Beijing Normal Univ, Minist Educ, Key Lab Cell Proliferat & Regulat Biol, Beijing 100875, Peoples R China

[12] Beijing Normal Univ, Coll Life Sci, Beijing 100875, Peoples R China

来源：

CANCER CELL | 2016年 / 30卷 / 03期

基金：

中国国家自然科学基金;

关键词：

UBIQUITIN-PROTEASOME PATHWAY; RENAL-CELL CARCINOMA; PROSTATE-CANCER; CLINICAL-TRIALS; PROTEIN; INHIBITORS; INACTIVATION; DEGRADATION; SPECIFICITY; COMPLEX;

D O I：

10.1016/j.ccell.2016.08.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

In the cytoplasm of virtually all clear-cell renal cell carcinoma (ccRCC), speckle-type POZ protein (SPOP) is overexpressed and misallocated, which may induce proliferation and promote kidney tumorigenesis. In normal cells, however, SPOP is located in the nucleus and induces apoptosis. Here we show that a structure-based design and subsequent hit optimization yield small molecules that can inhibit the SPOP-substrate protein interaction and can suppress oncogenic SPOP-signaling pathways. These inhibitors kill human ccRCC cells that are dependent on oncogenic cytoplasmic SPOP. Notably, these inhibitors minimally affect the viability of other cells in which SPOP is not accumulated in the cytoplasm. Our findings validate the SPOP-substrate protein interaction as an attractive target specific to ccRCC that may yield novel drug discovery efforts.

引用

页码：474 / 484

页数：11

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