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

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.

Immune defense of wild-caught Norway rats is characterized by increased levels of basal activity but reduced capability to respond to further immune stimulation

Studies of wild animals’immunity often use comparison with laboratory-raised individuals.Using such an approach,various data were obtained concerning wild Norway rat’s immunity.Lower or higher potential of immune system cells to respond to activation stimuli were shown,because of analysis of disparate parameters and/or small number of analyzed individuals.Inconsistent differences between laboratory and wild rats were shown too,owing to great response variability in wild rats.We hypothesized that wild rats will express more intense immune activity compared to their laboratory counterparts which live in a less demanding environment.To test this,we analyzed the circulating levels of inflammatory cytokine interleukin-6(IL-6),a mediator which has a central role in host immune defense.In addition,we examined the activity of the central immune organ,the spleen,including cell proliferation and production of pro-inflammatory cytokines interferon-γ(IFN-γ)and interleukin-17(IL-17),which are major effectors of cellular adaptive immune response.In order to obtain reasonable insight into the immunity of wild Norway rats,analysis was conducted on a much larger number of individuals compared to other studies.Higher levels of plasma IL-6,higher spleen mass,cellularity and basal IFN-γproduction concomitantly with lower basal production of anti-inflammatory cytokine interleukin-10(IL-10)revealed more intense immune activity in the wild compared to laboratory rats.However,lower responsiveness of their spleen cells’proinflammatory cytokine production to concanavalin A(ConA)stimulation,along with preserved capacity of IL-10 response,might be perceived as an indication of wild rats’reduced capability to cope with incoming environmental stimuli,but also as a means to limit tissue damage.