A Peptide Binder of E3 Ligase Adaptor SPOP Disrupts Oncogenic SPOP-Protein Interactions in Kidney Cancer Cells  

作　　者：Zhen Wang Hao Zhang Baoen Chen Sisheng Ouyang Tong Zheng Ran Zhou Ze Dong Yue Huang Tao Zhang Hualiang Jiang Jianhua Gan Cheng Luo Cai-Guang Yang 

机构地区：[1]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,Jiangsu,210023 China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203 China [3]University of Chinese Academy of Sciences,Beijing,100049 China [4]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou,Zhejiang,310024 China [5]Shanghai Institute for Advanced Immunochemical Studies,ShanghaiTech University,Shanghai,201210 China [6]School of Life Sciences,Fudan University,Shanghai,200433 China

出　　处：《Chinese Journal of Chemistry》2021年第2期274-280,共7页中国化学（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(No.21725801 to C.-G.Y,Nos.81625022 and 81430084 to C,L,and No.21807103 to 2.D.);the National Key New Urug Lreation and Manufacturing Program,Ministry of Science and Technology(No.20182X09711002 to Z.D.);the Science and Technology Commis-sion of Shanghal munltlpallty(NB.18YF1428500 to Y.H.alu Nu..18431907100 to H.J.J;the China Postdoctoral Science Foun-dation(No.2018M640434 to Y.H.,No.2017M621570 to Z.D.,and Nu.2018M032187 lwT.L).

摘　　要：The E3 ligase adaptor SPOP,overexpressed in the nucleus but frequently dislocated into the cytoplasm in all clear cell Renal Cell Carcinomas(ccRCC),serves as a regulatory hub to promote kidney cancer through the ubiquitination and degradation of multiple downstream cancer proteins.Recently,our identification of a selective small-molecule inhibitor of the SPOP-phosphatase and tensin homolog(PTEN)interaction has demonstrated that the oncogenic SPOP-protein interaction would be a druggable target specific to ccRCC therapy.To our knowledge,this is the first time such a small-molecule inhibitor has been developed.Herein,we have identified a peptide binder for the SPOP-MATH domain that disrupts the oncogenic SPOP-protein interactions in kidney cancer cells.Computational design and biophysical characterization yielded peptide Pep38 that binds to the MATH domain of SPOP and competes on PTEN-binding to SPOP in vitro.The X-ray complex structure reveals that the peptide binder features the following combination:one,a mimic of the native peptide binder and two,an additionalβ-strand motif in sequence,which could contribute to increased binding affinity.In order to improve cellular permeability,we fused Pep38 with the delivery peptide TAT to prepare peptide TAT38,which inhibits the endogenous substrate binding to SPOP and suppresses the proliferation of the ccRCC cells.Our identification of the peptide inhibitors for SPOP-protein interactions provides further validation that the oncogenic SPOP-signaling pathway in ccRCC could be a druggable target specifically applicable to the therapy of kidney cancers.

关 键 词：SPOP Protein-protein interaction Clear cell Renal Cell Carcinomas Crystal structure Peptide inhibitor 

分 类 号：R737.11[医药卫生—肿瘤]