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

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 ShaoYibin Kang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)43-59
Number of pages17
JournalNature Cancer
Volume3
Issue number1
DOIs
StatePublished - Jan 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research
  • Medicine(all)

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