Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

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 in vivo is yet to be discovered. Here, we developed a novel SIRT6 allosteric inhibitor, compound 11e, with maximal inhibitory potency and an IC50 value of 0.98 +/- 0.13 mmol/L. Moreover, compound 11e exhibited significant selectivity against other histone deacetylases (HADC1-11 and SIRT1-3) at concentrations up to 100 mmol/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 in vivo 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. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).