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

Qiufen ZHANG; Yingyi CHEN; Duan NI; Zhimin HUANG; Jiacheng WEI; Li FENG; Jun-Cheng SU; Yingqing WEI; Shaobo NING; Xiuyan YANG; Mingzhu ZHAO; Yuran QIU; Kun SONG; Zhengtian YU; Jianrong XU; Xinyi LI; Houwen LIN; Shaoyong LU; Jian ZHANG

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

Author: Qiufen ZHANG ¹ ; Yingyi CHEN ¹ ; Duan NI ¹ ; Zhimin HUANG ¹ ; Jiacheng WEI ¹ ; Li FENG ² ; Jun-Cheng SU ¹ ; Yingqing WEI ¹ ; Shaobo NING ¹ ; Xiuyan YANG ¹ ; Mingzhu ZHAO ¹ ; Yuran QIU ² ; Kun SONG ² ; Zhengtian YU ³ ; Jianrong XU ⁴ ; Xinyi LI ² ; Houwen LIN ¹ ; Shaoyong LU ¹ ; Jian ZHANG ¹
Author Information

1. State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
2. Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
3. Nutshell Therapeutics, Shanghai 201203, China.
4. Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Publication Type:Journal Article
Keywords: ADPr, ADP-ribose; Allosteric inhibitor; BSA, bull serum albumin; CCK-8, Cell Counting Kit-8; Cell migration; Cytokine production; DMSO, dimethyl sulfoxide; FBS, fetal bovine serum; FDL, Fluor de Lys; H3K18, histone 3 lysine 18; H3K56, histone 3 lysine 56; H3K9, histone 3 lysine 9; HDAC, histone deacetylase; HPLC, high-performance liquid chromatography; IC50, half-maximum inhibitory concentration; IPTG, isopropyl-β-d-thiogalactoside; MD, molecular dynamics; Molecular dynamics simulations; NAD+, nicotinamide adenine dinucleotide; NAM, nicotinamide; PBS, phosphate buffer saline; PMA, phorbol 12-myristate 13-acetate; PMSF, phenylmethanesulfonyl fluoride; Pancreatic cancer; RMSD, root-mean-square deviation; RT-qPCR, real-time quantitative PCR; Reversed allostery; SDS-PAGE, SDS-polyacrylamide gel electrophoresis; SIRT6; SIRT6, sirtuin 6
From: Acta Pharmaceutica Sinica B 2022;12(2):876-889
CountryChina
Language:English
Abstract: 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.