Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer.
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.
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Department of Urology, Peking University First Hospital, Beijing 100034, China; Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Zhong-Qiang
ZQ
Guo
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Tong
T
Zheng
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Baoen
B
Chen
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cheng
C
Luo
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Sisheng
S
Ouyang
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Shouzhe
S
Gong
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jiafei
J
Li
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
Liu-Liang
LL
Mao
Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Fulin
F
Lian
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yong
Y
Yang
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Yue
Y
Huang
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Li
L
Li
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jing
J
Lu
University of Chinese Academy of Sciences, Beijing 100049, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Bidong
B
Zhang
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Luming
L
Zhou
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Hong
H
Ding
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Zhiwei
Z
Gao
Department of Urology, Peking University First Hospital, Beijing 100034, China.
Liqun
L
Zhou
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Guoqiang
G
Li
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Ran
R
Zhou
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Ke
K
Chen
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jingqiu
J
Liu
Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yi
Y
Wen
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Likun
L
Gong
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
Yuwen
Y
Ke
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
Shang-Dong
SD
Yang
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Xiao-Bo
XB
Qiu
Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Naixia
N
Zhang
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jin
J
Ren
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Dafang
D
Zhong
Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: yangcg@simm.ac.cn.
Cai-Guang
CG
Yang
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liuj@big.ac.cn.
Jiang
J
Liu
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hljiang@simm.ac.cn.
Hualiang
H
Jiang
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases