1.Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells.
Qiufen ZHANG ; Yingyi CHEN ; Duan NI ; Zhimin HUANG ; Jiacheng WEI ; Li FENG ; Jun-Cheng SU ; Yingqing WEI ; Shaobo NING ; Xiuyan YANG ; Mingzhu ZHAO ; Yuran QIU ; Kun SONG ; Zhengtian YU ; Jianrong XU ; Xinyi LI ; Houwen LIN ; Shaoyong LU ; Jian ZHANG
Acta Pharmaceutica Sinica B 2022;12(2):876-889
SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.
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