典型文献
Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells
文献摘要：
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.
文献关键词：
中图分类号：
作者姓名：
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
作者机构：
State Key Laboratory of Oncogenes and Related Genes,Department of Pharmacy,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China;Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Nutshell Therapeutics,Shanghai 201203,China;Academy of Integrative Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China
文献出处：
引用格式：
[1]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-.Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells)[J].药学学报（英文版）,2022(02):876-889
A类：
orthosteric,AlloRe,JYQ,deace,tylases
B类：
Targeting,cryptic,allosteric,SIRT6,small,molecule,inhibitors,that,migration,pancreatic,cancer,cells,belongs,conserved,NAD+,dependent,superfamily,mediates,multiple,biological,pathological,processes,by,modulators,represents,novel,therapeutics,which,overcome,selectivity,problem,caused,structural,sim,ilarity,sites,among,deacetylases,Here,developing,reversed,strategy,we,identified,Pocket,was,only,induced,directional,signal,triggered,upon,binding,Based,discovered,named,selectively,targets,other,histone,effectively,inhibits,deacetylation,IC50,significantly,suppresses,mediated,inflammatory,cytokine,production,our,knowledge,most,potent,This,study,provides,drug,design,will,help,challenging,development,agents
AB值：
0.495724
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