Affiliation:
1. Department of Biochemistry University of Bayreuth Universitaetsstr. 30 95447 Bayreuth Germany
2. Department of Medicinal Chemistry Skaggs College of Pharmacy University of Utah 30 S 2000 E Salt Lake City UT 84112 USA
3. Huntsman Cancer Institute University of Utah 2000 Circle of Hope Salt Lake City UT 84112 USA
Abstract
AbstractSirtuin 6 (Sirt6), an NAD+‐dependent deacylase, has emerged as a promising target for aging‐related diseases and cancer. Advancing the medicinal chemistry of Sirt6 modulators is crucial for the development of chemical probes aimed at unraveling the intricate biological functions of Sirt6 and unlocking its therapeutic potential. A proprietary DNA‐encoded library yielded Sirt6 inhibitor 2‐Pr, displaying remarkable inhibitory activity and isoform‐selectivity, and featuring a chemical structure distinct from reported Sirt6 modulators. In this study, we explore the inhibitory mechanism of 2‐Pr, evaluating the impact of chemical modifications and presenting a crystal structure of the Sirt6/ADP‐ribose/2‐Pr complex. Notably, co‐crystal structure analysis reveals an unexpected and unprecedented binding mode of Sirt6, with 2‐Pr spanning the acyl channel of the enzyme, extending into the acetyl‐lysine binding pocket, and reaching toward the C‐site. This unique binding mode guides potential avenues for developing potent and selective Sirt6 inhibitors.