Elucidating the Unconventional Binding Mode of a DNA‐Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development

• Published in: ChemMedChem Vol. 19; no. 20; pp. e202400273 - n/a
• Main Authors: You, Weijie, Montoya, Alba L., Dana, Srikanta, Franzini, Raphael M., Steegborn, Clemens
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 16.10.2024
• Subjects: Acyl binding pocket; Adenosine diphosphate; Binding; Binding Sites; Chemical activity; Crystal structure; Crystallography, X-Ray; Deacylase; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; DNA probes; DNA-encoded chemical libraries; Dose-Response Relationship, Drug; Drug Development; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gene Library; Humans; Inhibitors; Lysine; Models, Molecular; Modulators; Molecular Structure; Ribose; Sirt6 inhibition; Sirtuins - antagonists & inhibitors; Sirtuins - chemistry; Sirtuins - metabolism; Structural analysis; Structure-Activity Relationship; Sirt6 inhibition; Deacylase; Acyl binding pocket; DNA-encoded chemical libraries; Crystal structure
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202400273

Sirtuin 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. This study explores the mechanism and medicinal chemistry of 2‐Pr, a highly potent and selective inhibitor of the protein deacylase Sirtuin 6. We evaluate the impact of chemical modifications and present a crystal structure of the Sirt6/ADP‐ribose/2‐Pr complex, which reveals an unexpected and unprecedented binding mode. This unique binding mode guides potential avenues for developing potent and selective Sirt6 inhibitors.