Elucidating the Unconventional Binding Mode of a DNA‐Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development
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 unlocki...
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Published in | ChemMedChem Vol. 19; no. 20; pp. e202400273 - n/a |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
Wiley Subscription Services, Inc
16.10.2024
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | W. You and A. L. Montoya contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1860-7179 1860-7187 1860-7187 |
DOI: | 10.1002/cmdc.202400273 |