Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.

Abstract

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

• Authors: Minhong Shen, Yong Wei, Hahn Kim, Liling Wan, Yi-Zhou Jiang, Xiang Hang, Michael Raba, Stacy Remiszewski, Michelle Rowicki, Cheng-Guo Wu, Songyang Wu, Lanjing Zhang, Xin Lu, Min Yuan, Heath A Smith, Aiping Zheng, Joseph Bertino, John F Jin, Yongna Xing, Zhi-Ming Shao, Yibin Kang
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 1 Pg. 43-59 (01 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 35121987 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Cell Adhesion Molecules
• MTDH protein, human
• Membrane Proteins
• Mtdh protein, mouse
• RNA-Binding Proteins
• Transcription Factors
• Endonucleases
• SND1 protein, human
• Snd1 protein, mouse
• Micrococcal Nuclease

Topics

• Animals
• Cell Adhesion Molecules (genetics)
• Endonucleases (metabolism)
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Micrococcal Nuclease
• RNA-Binding Proteins (genetics, metabolism)
• Transcription Factors
• Triple Negative Breast Neoplasms