P53 upregulation by USP7-engaging molecular glues

• DOI: 10.1016/j.scib.2024.04.017
• Publication Date: 2024-04-11T01:14:38Z
• Authors: 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

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