8I2B
Human SIRT6 in complex with inhibitor 7702
Summary for 8I2B
| Entry DOI | 10.2210/pdb8i2b/pdb |
| Descriptor | 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) |
| Functional Keywords | lyase-inhibitor complex, lyase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 67761.58 |
| Authors | Wang, Y. (deposition date: 2023-01-14, release date: 2024-01-17, Last modification date: 2025-07-30) |
| Primary citation | 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 Cited by 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: 38487000DOI: 10.1016/j.apsb.2023.11.014 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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