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

Minhong Shen1, Yong Wei1, Hahn Kim2,3

  • 1Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

Nature Cancer
|February 5, 2022
PubMed

Insights

Targeting metadherin (MTDH) and its interaction with SND1 shows promise for treating metastatic breast cancer. Inhibiting this complex suppressed tumor growth and metastasis in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Metastatic breast cancer presents a significant global health challenge.
  • Metadherin (MTDH) is implicated in promoting breast cancer initiation, metastasis, and therapeutic resistance.
  • The therapeutic strategies targeting MTDH are underexplored.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting the metadherin (MTDH) protein.
  • To explore the role of the MTDH-staphylococcal nuclease domain-containing 1 (SND1) interaction in breast cancer progression.
  • To identify novel therapeutic agents for metastatic breast cancer.

Main Methods:

  • Utilized genetically modified mice to study the effects of Mtdh ablation.
  • Conducted small-molecule compound screening to identify inhibitors of the MTDH-SND1 protein-protein interaction (PPI).
  • Evaluated lead compounds in preclinical models of triple-negative breast cancer (TNBC).

Main Results:

  • Genetic ablation of Mtdh inhibited breast cancer development by disrupting the MTDH-SND1 interaction.
  • Identified specific small-molecule inhibitors (C26-A2 and C26-A6) that disrupt the MTDH-SND1 PPI.
  • These compounds suppressed tumor growth and metastasis while enhancing chemotherapy sensitivity in TNBC models.

Conclusions:

  • Targeting the MTDH-SND1 complex represents a promising therapeutic strategy for metastatic breast cancer.
  • The identified small-molecule inhibitors offer a new class of potential therapeutic agents for TNBC.
  • Disrupting the MTDH-SND1 interaction is a viable approach to combatting breast cancer progression and therapy resistance.

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