Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells.
Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells.
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使用抑制胰腺癌细胞迁移的小分子抑制剂靶向 SIRT6 的隐秘变构位点
DOI：
10.1016/j.apsb.2021.06.015
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhang Q;Chen Y;Ni D;Huang Z;Wei J;Feng L;Su JC;Wei Y;Ning S;Yang X;Zhao M;Qiu Y;Song K;Yu Z;Xu J;Li X;Lin H;Lu S;Zhang J
SIRT 6属于保守的NAD+依赖性脱乙酰酶超家族，介导多种生物学和病理学过程。通过变构调节剂靶向SIRT 6代表了治疗的新方向，其可以克服由脱乙酰酶之间的正构位点的结构相似性引起的选择性问题。在这里，开发了一种反向变构策略AlloReverse，我们确定了一个隐藏的变构位点，口袋Z，它只由NAD+的正构结合后触发的双向变构信号诱导。基于Pocket Z，我们发现了一种名为JYQ-42的SIRT 6变构抑制剂。JYQ-42在其他组蛋白脱乙酰酶中选择性靶向SIRT 6，并有效抑制SIRT 6的脱乙酰化，IC 50为2.33 μmol/L。JYQ-42显著抑制SIRT 6介导的癌细胞迁移和促炎细胞因子产生。据我们所知，JYQ-42是最有效和选择性的变构SIRT 6抑制剂。这项研究为变构药物设计提供了一种新的策略，并将有助于开发具有挑战性的治疗药物，可以选择性地结合SIRT 6。在SIRT 6内诱导了一个新的变构口袋Z，并合理设计了第一个选择性SIRT 6变构抑制剂JYQ-42。JYQ-42在胰腺癌细胞系中表现出有希望的功效。
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. A novel allosteric Pocket Z within SIRT6 was induced and the first selective SIRT6 allosteric inhibitor JYQ-42 was rationally designed. JYQ-42 exhibits promising efficacy in pancreatic cancer cell lines.
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影响因子：
4.8
作者：
Liszt, G;Ford, E;Guarente, L
通讯作者：
Guarente, L
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3
作者：
Le Guilloux V;Schmidtke P;Tuffery P
通讯作者：
Tuffery P
DOI：
10.13345/j.cjb.150403
发表时间：
2016-07-25
期刊：
Sheng wu gong cheng xue bao = Chinese journal of biotechnology
影响因子：
--
作者：
Dong, Zhen;Lei, Qian;Cui, Hongjuan
通讯作者：
Cui, Hongjuan
影响因子：
5.5
作者：
Bucher, Denis;Pierce, Levi C. T.;McCammon, J. Andrew;Markwick, Phineus R. L.
通讯作者：
Markwick, Phineus R. L.