8I2B

Human SIRT6 in complex with inhibitor 7702

8I2B の概要

• エントリーDOI: 10.2210/pdb8i2b/pdb
• 分子名称: NAD-dependent protein deacylase sirtuin-6, TETRAETHYLENE GLYCOL, N1-[[4-(4-aminophenyl)sulfanyl-3-(trifluoromethyl)phenyl]methoxy]benzene-1,4-dicarboxamide, ... (7 entities in total)
• 機能のキーワード: lyase-inhibitor complex, lyase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67761.58

構造登録者

Wang, Y. (登録日: 2023-01-14, 公開日: 2024-01-17, 最終更新日: 2025-07-30)

主引用文献

Xu, X.,Zhang, Q.,Wang, X.,Jin, J.,Wu, C.,Feng, L.,Yang, X.,Zhao, M.,Chen, Y.,Lu, S.,Zheng, Z.,Lan, X.,Wang, Y.,Zheng, Y.,Lu, X.,Zhang, Q.,Zhang, J.
Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo.
Acta Pharm Sin B, 14:1302-1316, 2024

PubMed Abstract: Pancreatic cancer, one of the most aggressive malignancies, has no effective treatment due to the lack of targets and drugs related to tumour metastasis. SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer. However, highly selective and potency SIRT6 inhibitor that can be used is yet to be discovered. Here, we developed a novel SIRT6 allosteric inhibitor, compound , with maximal inhibitory potency and an IC value of 0.98 ± 0.13 μmol/L. Moreover, compound exhibited significant selectivity against other histone deacetylases (HADC1‒11 and SIRT1‒3) at concentrations up to 100 μmol/L. The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses. Importantly, we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis. To our knowledge, this is the first study to reveal the effects of SIRT6 inhibitors on liver metastatic pancreatic cancer. It not only provides a promising lead compound for subsequent inhibitor development targeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

PubMed: 38487000
DOI: 10.1016/j.apsb.2023.11.014

実験手法

X-RAY DIFFRACTION (2.2 Å)