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 

机构地区：[1]State Key Laboratory of Oncogenes and Related Genes,Department of Pharmacy,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [2]Medicinal Chemistry and Bioinformatics Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [3]Nutshell Therapeutics,Shanghai 201203,China [4]Academy of Integrative Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [5]School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第2期876-889,共14页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81925034,81903458,22077082,82003605,81901423);the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00036,China);Shanghai Science and Technology Innovation Fundation(19431901600,China);the Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program(2018BR12,China);Special Financial Grant of Postdoctoral Research Foundation of China(2019M660090);。

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 similarity of orthosteric sites among deacetylases.Here,developing a reversed allosteric strategy Allo Reverse,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 2.33μmol/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.

关 键 词：SIRT6 Molecular dynamics simulations Reversed allostery Allosteric inhibitor Pancreatic cancer Cell migration Cytokine production 

分 类 号：R91[医药卫生—药学]