【摘 要】
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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 pro
【机 构】
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State Key Laboratory of Oncogenes and Related Genes,Department of Pharmacy,Renji Hospital,Shanghai J
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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.
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