Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells

• 作者: 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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2022,（2）
• 所属期刊栏目: Original articles
• 页码范围: 876-889
• 页数: 14页
• 语种: 英文

摘要

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 sim-ilarity of orthosteric sites among deacetylases.Here,developing a reversed allosteric strategy AlloRe-verse,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 deace-tylases 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.