7KNX

Crystal structure of SND1 in complex with C-26-A6

Summary for 7KNX

• Entry DOI: 10.2210/pdb7knx/pdb
• Descriptor: Staphylococcal nuclease domain-containing protein 1, TYROSINE, 5-chloro-2-methoxy-N-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide, ... (5 entities in total)
• Functional Keywords: inhibitor, endonuclease, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 148872.45

Authors

Kang, Y. (deposition date: 2020-11-06, release date: 2021-12-08, Last modification date: 2024-05-22)

Primary citation

Shen, 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, H.A.,Zheng, A.,Bertino, J.,Jin, J.F.,Xing, Y.,Shao, Z.M.,Kang, Y.
Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.
Nat Cancer, 3:43-59, 2022

PubMed 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.

PubMed: 35121987
DOI: 10.1038/s43018-021-00279-5

Experimental method

X-RAY DIFFRACTION (2.7 Å)