通过USP7结合分子胶上调P53蛋白  

P53 upregulation by USP7-engaging molecular glues

作　　者：李朝阳 王紫英 钟超 张航 刘瑞 安平 马志强 卢俊梅 潘成芳 张兆霖 曹志远 胡健一 邢栋 费一艳 丁澦 鲁伯埙 Zhaoyang Li;Ziying Wang;Chao Zhong;Hang Zhang;Rui Liu;Ping An;Zhiqiang Ma;Junmei Lu;Chengfang Pan;Zhaolin Zhang;Zhiyuan Cao;Jianyi Hu;Dong Xing;Yiyan Fei;Yu Ding;Boxun Lu(The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Huashan Hospital,the Institutes of Brain Science,School of Life Sciences,Fudan University,Shanghai 200438,China;Department of Optical Science and Engineering,Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing,Key Laboratory of Micro and Nano Photonic Structures(Ministry of Education),Fudan University,Shanghai 200438,China;Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200241,China)

机构地区：[1]The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Huashan Hospital,the Institutes of Brain Science,School of Life Sciences,Fudan University,Shanghai 200438,China [2]Department of Optical Science and Engineering,Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing,Key Laboratory of Micro and Nano Photonic Structures(Ministry of Education),Fudan University,Shanghai 200438,China [3]Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200241,China

出　　处：《Science Bulletin》2024年第12期1936-1953,共18页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82050008,92049301,81925012,32200797,32271510,32200602,and 82030106);the Science and Technology Commission of Shanghai Municipality(20JC1410900);Shanghai Municipal Science and Technology Key Laboratory Project(23dz2260100);the Innovation Program of Shanghai Municipal Education Commission(2021-01-07-00-07-E00074);the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01);the China Postdoctoral Science Foundation(BX20200093 and 2021M690038)。

摘　　要：Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation.Identifying molecular glues is challenging.There is a scarcity of target-specific upregulating molecular glues,which are highly anticipated for numerous targets,including P53.P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases,whereas deubiquitinases(DUBs)remove polyubiquitination conjugates to counteract these E3ligases.Thus,small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination.Here,using small-molecule microarray-based technology and unbiased screening,we identified three potential molecular glues that may tether P53 to the DUB,USP7,and elevate the P53 level.Among the molecular glues,bromocriptine(BC)is an FDA-approved drug with the most robust effects.BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7.Consistent with P53 upregulation in cancer cells,BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model.In summary,we established a potential screening platform and identified potential molecular glues upregulating P53.Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.

关 键 词：P53 USP7 DEUBIQUITINATION UPREGULATION 

分 类 号：Q75[生物学—分子生物学]