Discovery of SIRT7 Inhibitor as New Therapeutic Options Against Liver Cancer.
Discovery of SIRT7 Inhibitor as New Therapeutic Options Against Liver Cancer.
复制标题
SIRT7抑制剂作为肝癌新的治疗选择的发现。
DOI：
10.3389/fcell.2021.813233
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发表时间：
2021
影响因子：
5.5
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Zhang C;Li Y;Liu B;Ning C;Li Y;Wang Y;Li Z
由于手术切除后的高复发率和化疗耐药，肝癌患者的最佳治疗策略仍然具有挑战性。新出现的证据表明，表观遗传因子SIRT 7参与癌症生物学的各个方面，而失活的SIRT 7逆转人类癌症表型并抑制肿瘤生长。在本研究中，我们通过使用折叠识别（或线程）方法预测SIRT 7结构，并进行基于结构的虚拟筛选，通过将939319个结构不同的化合物与SIRT蛋白对接来开发特异性SIRT 7抑制剂。选择对SIRT 7具有高亲和力但对其他SIRT蛋白具有低亲和力的化合物作为特异性SIRT 7抑制剂的候选物。我们的先导化合物2800 Z和40569 Z显示出与SIRT 7蛋白的强相互作用，并在体外特异性抑制SIRT 7去乙酰化活性。我们的对接结果还表明，ARG-120，TRP-126和HIS-187是负责SIRT 7与小分子相互作用的关键位点。上述位点的突变显著消除了化合物对SIRT 7的相互作用和抑制作用。此外，体内数据表明，化合物2800 Z和40569 Z能够诱导细胞凋亡并增加人肝癌对索拉非尼的化学敏感性。我们的研究结果表明，靶向SIRT 7可能为癌症管理提供新的治疗选择，化合物2800 Z和40569 Z作为研究SIRT 7生物学功能的化学探针的价值，以及开发新的肝癌治疗选择的起点。
Optimal therapeutic strategies for liver cancer patients remain challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Emerging evidence has shown that epigenetic factor SIRT7 is involved in various aspects of cancer biology, while inactive SIRT7 reverses human cancer phenotype and suppresses tumor growth. In the present study, we predicted the SIRT7 structure by using the fold recognition (or threading) method and performed structure-based virtual screening to develop specific SIRT7 inhibitor by docking 939319 structurally diverse compounds with SIRT proteins. Compounds with high affinities to SIRT7 but low affinities to other SIRT proteins were chosen as candidates of specific SIRT7 inhibitor. Our leading compounds 2800Z and 40569Z showed strong interaction with SIRT7 protein, and specifically inhibited SIRT7 deacetylation activity in vitro. Our docking results also revealed that ARG-120, TRP-126, and HIS-187 were critical sites responsible for interaction of SIRT7 with small molecules. Mutations in the aforementioned sites significantly abolished interaction and inhibitory effects of compounds to SIRT7. In addition, in vivo data indicated that compounds 2800Z and 40569Z were able to induce apoptosis and increase chemosensitivity to sorafenib in human liver cancer. Our findings demonstrated targeting SIRT7 may offer novel therapeutic options for cancer management, and the value of compounds 2800Z and 40569Z as chemical probes for the study of SIRT7 biological functions as well as starting leads for the development of new therapeutic options against liver cancer.
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影响因子：
254.7
作者：
Miller, Kimberly D.;Fidler-Benaoudia, Miranda;Siegel, Rebecca L.
通讯作者：
Siegel, Rebecca L.
影响因子：
3.9
作者：
Dyhl-Polk A;Mikkelsen MK;Ladekarl M;Nielsen DL
通讯作者：
Nielsen DL
DOI：
10.1016/j.bbrc.2018.11.120
发表时间：
2019-01-08
影响因子：
3.1
作者：
Kim, Ji-Hye;Kim, Dahee;Kim, Kwang Rol
通讯作者：
Kim, Kwang Rol
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Barber, Matthew F.;Michishita-Kioi, Eriko;Xi, Yuanxin;Tasselli, Luisa;Kioi, Mitomu;Moqtaderi, Zarmik;Tennen, Ruth I.;Paredes, Silvana;Young, Nicolas L.;Chen, Kaifu;Struhl, Kevin;Garcia, Benjamin A.;Gozani, Or;Li, Wei;Chua, Katrin F.
通讯作者：
Chua, Katrin F.