4.7 Article

A small-molecule Skp 1 inhibitor elicits cell death by p53-dependent mechanism

期刊

ISCIENCE
卷 25, 期 7, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.isci.2022.104591

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资金

  1. National Key Research and Development Program [2017YFA0504104]
  2. Project of State Key Laboratory of Respiratory Disease [SKLRD-QN-201712]
  3. Guangdong Provincial Key Laboratory of Biocomputing [2016B030301007]
  4. Frontier Research Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) [2018GRZ110105017]
  5. Guangdong Provincial Postdoctoral Special Funding
  6. Huangpu District Postdoctoral Research Startup Fund
  7. CAS-TWAS President's Fellowship for International PhD students
  8. Guangzhou Branch of the Supercomputing Center of Chinese Academy of Sciences

向作者/读者索取更多资源

Skp1 overexpression promotes tumor growth, while reduced Skp1 activity is linked to genomic instability and neoplastic transformation. This study identifies Z0933M as a potent Skp1 inhibitor that disrupts SCF E3 ligase functioning and induces cell death. Z0933M could be a valuable tool for exploring Skp1 cancer biology and has implications for cancer therapy.
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 K-D similar to 0.054 mu M. 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.

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