| 论文编号: |
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| 第一作者所在部门: |
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| 中文论文题目: |
A small-molecule Skp1 inhibitor elicits cell death by p53-dependent mechanism |
| 英文论文题目: |
A small-molecule Skp1 inhibitor elicits cell death by p53-dependent mechanism |
| 作者: |
Muzammal Hussain, Yongzhi Lu, Muqddas Tariq, Hao Jiang, Yahai Shu, Shuang Luo, Qiang Zhu, Jiancun Zhang, and Jinsong Liu |
| 论文出处: |
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| 刊物名称: |
iScience |
| 年: |
2022 |
| 卷: |
25 |
| 期: |
7 |
| 页: |
104591 |
| 联系作者: |
Jinsong Liu |
| 收录类别: |
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| 影响因子: |
6.107 |
| 摘要: |
Skp1 overexpression promotes tumor growth, whereas reduced Skp1 activity is also linked with genomic instability and neoplastic transformation. This highlights the need to gain better understanding of Skp1 biology in cancer settings. To this context, potent and cellularly active small-molecule Skp1 inhibitors may be of great value. Using a hypothesis-driven, structure-guided approach, we herein identify Z0933M as a potent Skp1 inhibitor with KD ～0.054 μM. Z0933M occupies a hydrophobic hotspot (P1) - encompassing an aromatic cage of two phenylalanines (F101 and F139) - alongside C-terminal extension of Skp1 and, thus, hampers its ability to interact with F-box proteins, a prerequisite step to constitute intact and active SCF E3 ligase(s) complexes. In cellulo, Z0933M disrupted SCF E3 ligase(s) functioning, recapitulated previously reported effects of Skp1-reduced activity, and elicited cell death by a p53-dependent mechanism. We propose Z0933M as valuable tool for future efforts toward probing Skp1 cancer biology, with implications for cancer therapy. |
| 英文摘要: |
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