7KNX

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

7KNX の概要

• エントリーDOI: 10.2210/pdb7knx/pdb
• 分子名称: 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)
• 機能のキーワード: inhibitor, endonuclease, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 148872.45

構造登録者

Kang, Y. (登録日: 2020-11-06, 公開日: 2021-12-08, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.7 Å)