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

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2024 Jun 28

PMID 38940296

Authors

Weijie You

Alba L Montoya

Srikanta Dana

Raphael M Franzini

Clemens Steegborn

Affiliations

Soon will be listed here.

Abstract

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.

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