Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells

• Main Authors: Qiufen Zhang (Author), Yingyi Chen (Author), Duan Ni (Author), Zhimin Huang (Author), Jiacheng Wei (Author), Li Feng (Author), Jun-Cheng Su (Author), Yingqing Wei (Author), Shaobo Ning (Author), Xiuyan Yang (Author), Mingzhu Zhao (Author), Yuran Qiu (Author), Kun Song (Author), Zhengtian Yu (Author), Jianrong Xu (Author), Xinyi Li (Author), Houwen Lin (Author), Shaoyong Lu (Author), Jian Zhang (Author)
• Format: Book
• Published: Elsevier, 2022-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Item Description

2211-3835
10.1016/j.apsb.2021.06.015