SIRT6 is a member of the sirtuin family and has been recently shown to be crucial for a number of processes including telomere maintenance, DNA repair and genome stability, secretion of inflammatory cytokines, regulation of glycemia and epigenetic control of acetylated histones.Based on the crystal structure of SIRT6 and by means of structure-based molecular design techniques, we identified several scaffolds as good binders of SIRT6. Drug-like analogs of these scaffolds were revealed to inhibit SIRT6 with a considerable selectivity (more than 20-fold) over SIRT1 and SIRT2. We will discuss the synthesis and biological characterization of these inhibitors as well as the molecular determinants for the design of SIRT6-selective inhibitors.These inhibitors may have properties to sensitize cancer cells to chemotherapeutics, treat aging-related pathologies, act as anti-inflammatory compounds or as glucose-lowering agents with potential clinical values.

Design, synthesis and biological evaluation of novel and selective SIRT6 inhibitors

247th National Meeting (2014)

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