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

TitleSmall-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.
Publication TypeJournal Article
Year of Publication2022
AuthorsShen, M, Wei, Y, Kim, H, Wan, L, Jiang, Y-Z, Hang, X, Raba, M, Remiszewski, S, Rowicki, M, Wu, C-G, Wu, S, Zhang, L, Lu, X, Yuan, M, Smith, HA, Zheng, A, Bertino, J, Jin, JF, Xing, Y, Shao, Z-M, Kang, Y
JournalNat Cancer
Volume3
Issue1
Pagination43-59
Date Published2022 01
ISSN2662-1347
KeywordsAnimals, Cell Adhesion Molecules, Endonucleases, Humans, Membrane Proteins, Mice, Micrococcal Nuclease, RNA-Binding Proteins, Transcription Factors, Triple Negative Breast Neoplasms
Abstract

<p>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.</p>

DOI10.1038/s43018-021-00279-5
Alternate JournalNat Cancer
PubMed ID35121987
PubMed Central IDPMC8818087
Grant ListP30 CA072720 / CA / NCI NIH HHS / United States
R01 CA134519 / CA / NCI NIH HHS / United States