P53 upregulation by USP7-engaging molecular glues

扫码查看

原文链接

NETL
NSTL
万方数据

外文摘要：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 challeng-ing.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 E3 ligases.Thus,small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deu-biquitination.Here,using small-molecule microarray-based technology and unbiased screening,we iden-tified 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.

外文关键词：

P53USP7DeubiquitinationUpregulation

作者：

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

展开 >

作者单位：

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

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaScience and Technology Commission of Shanghai MunicipalityShanghai Municipal Science and Technology Key Laboratory ProjectInnovation Program of Shanghai Municipal Education CommissionShanghai Municipal Science and Technology Major ProjectChina Postdoctoral Science FoundationChina Postdoctoral Science Foundation

项目编号：

8205000892049301819250123220079732271510322006028203010620JC141090023dz22601002021-01-07-00-07-E000742018SHZDZX01BX202000932021M690038

出版年：

2024

DOI：

10.1016/j.scib.2024.04.017

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

年,卷(期)：2024.69(12)