The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold.
The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold.
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DOI：
10.1038/s41419-017-0259-1
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Brancolini C
中科院分区：
文献类型：
--
作者：
Ciotti S;Sgarra R;Sgorbissa A;Penzo C;Tomasella A;Casarsa F;Benedetti F;Berti F;Manfioletti G;Brancolini C
具有可接近的β-碳的二芳基二烯酮衍生物显示出强的抗肿瘤性质，这与它们通过迈克尔加成与游离硫醇形成共价加合物的能力有关，并且在体内具有低毒性。聚泛素化蛋白的积累、未折叠蛋白反应（UPR）的激活和细胞死亡的诱导是其活性的普遍标志。这些化合物已被表征为异肽酶的抑制剂，异肽酶是半胱氨酸蛋白酶家族，其使泛素和泛素样蛋白与其靶标去缀合。然而，目前还不清楚它们是否也可以与其他蛋白质反应。在这项工作中，我们利用名为2c的生物素共轭二芳基二烯酮衍生物作为诱饵来纯化这些小分子的新细胞靶点。蛋白质组学分析已经揭示，除了异肽酶，这些抑制剂可以与不同的细胞内蛋白质形成稳定的共价加合物，从而潜在地影响细胞的多种功能，从细胞骨架组织到代谢。这些广泛的活性可以解释二芳基二烯酮衍生物有效触发不同细胞死亡途径的能力。
Diaryldienone derivatives with accessible β-carbons show strong anti-neoplastic properties, related to their ability to make covalent adducts with free thiols by Michael addition, and low toxicity in vivo. Accumulation of poly-ubiquitylated proteins, activation of the unfolded protein response (UPR) and induction of cell death are universal hallmarks of their activities. These compounds have been characterized as inhibitors of isopeptidases, a family of cysteine-proteases, which de-conjugate ubiquitin and ubiquitin-like proteins from their targets. However, it is unclear whether they can also react with additional proteins. In this work, we utilized the biotin-conjugated diaryldienone-derivative named 2c, as a bait to purify novel cellular targets of these small molecules. Proteomic analyses have unveiled that, in addition to isopeptidases, these inhibitors can form stable covalent adducts with different intracellular proteins, thus potentially impacting on multiple functions of the cells, from cytoskeletal organization to metabolism. These widespread activities can explain the ability of diaryldienone derivatives to efficiently trigger different cell death pathways.
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影响因子：
9.9
作者：
通讯作者：
--
影响因子：
4.5
作者：
Di Giorgio E;Franforte E;Cefalù S;Rossi S;Dei Tos AP;Brenca M;Polano M;Maestro R;Paluvai H;Picco R;Brancolini C
通讯作者：
Brancolini C
影响因子：
50.3
作者：
Anchoori RK;Karanam B;Peng S;Wang JW;Jiang R;Tanno T;Orlowski RZ;Matsui W;Zhao M;Rudek MA;Hung CF;Chen X;Walters KJ;Roden RB
通讯作者：
Roden RB
影响因子：
7.3
作者：
Cersosimo, Ulma;Sgorbissa, Andrea;Brancolini, Claudio
通讯作者：
Brancolini, Claudio
DOI：
10.1074/mcp.m111.014050
发表时间：
2012-03
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Geiger T;Wehner A;Schaab C;Cox J;Mann M
通讯作者：
Mann M