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USP7 结合分子胶上调 P53。

P53 upregulation by USP7-engaging molecular glues.

机构信息

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.

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.

出版信息

Sci Bull (Beijing). 2024 Jun 30;69(12):1936-1953. doi: 10.1016/j.scib.2024.04.017. Epub 2024 Apr 11.


DOI:10.1016/j.scib.2024.04.017
PMID:38734583
Abstract

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 E3 ligases. 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.

摘要

分子胶通常是小的化学分子,作用于靶蛋白和降解机制之间的界面,触发三元复合物的形成。鉴定分子胶具有挑战性。目前缺乏针对特定靶标的上调分子胶,而针对许多靶标,包括 P53,人们对此类分子胶的需求很高。P53 通过特定的 E3 连接酶通过多泛素化在蛋白酶体中降解,而去泛素化酶 (DUBs) 则去除多泛素化缀合物以对抗这些 E3 连接酶。因此,增强 P53 与 DUB 结合的小分子胶可能通过去泛素化稳定 P53。在这里,我们使用基于小分子微阵列的技术和无偏筛选,鉴定了三种可能将 P53 与 DUB、USP7 结合并提高 P53 水平的潜在分子胶。在这些分子胶中,溴隐亭 (BC) 是一种具有最显著效果的 FDA 批准药物。BC 进一步通过预测的分子胶机制与 USP7 结合被证明可以增加 P53 的稳定性。与癌细胞中 P53 的上调一致,BC 被证明可以在体外抑制癌细胞的增殖,并抑制异种移植模型中的肿瘤生长。总之,我们建立了一个潜在的筛选平台,并鉴定了潜在的上调 P53 的分子胶。类似的策略可应用于鉴定其他类型的分子胶,这些分子胶可能有益于药物发现和化学生物学研究。

相似文献

[1]
P53 upregulation by USP7-engaging molecular glues.

Sci Bull (Beijing). 2024-6-30

[2]
Molecular basis of USP7 inhibition by selective small-molecule inhibitors.

Nature. 2017-10-26

[3]
FAM188B enhances cell survival via interaction with USP7.

Cell Death Dis. 2018-5-24

[4]
Discovery of a Potent and Selective Degrader for USP7.

Angew Chem Int Ed Engl. 2022-8-15

[5]
TSPY1 suppresses USP7-mediated p53 function and promotes spermatogonial proliferation.

Cell Death Dis. 2018-5-1

[6]
Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism.

Sci Rep. 2020-3-24

[7]
Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.

Aging Cell. 2020-3

[8]
Inhibition of USP7 induces p53-independent tumor growth suppression in triple-negative breast cancers by destabilizing FOXM1.

Cell Death Differ. 2023-7

[9]
Inhibition of USP7 suppresses advanced glycation end-induced cell cycle arrest and senescence of human umbilical vein endothelial cells through ubiquitination of p53.

Acta Biochim Biophys Sin (Shanghai). 2022-3-25

[10]
USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma.

Oncogene. 2022-11

引用本文的文献

[1]
Molecular regulation by ubiquitin-specific proteases (USPs) in HCC: cell cycle, oncogenic signaling, and beyond.

Naunyn Schmiedebergs Arch Pharmacol. 2025-7-23

[2]
The potential value of microRNA-409-5p-mediated negative regulation of USP7 in the diagnosis and treatment of acute myocardial infarction.

BMC Cardiovasc Disord. 2025-3-8

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