Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity,ACS Chemical Biology

当前位置： X-MOL 学术 › ACS Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-09-13 00:00:00 , DOI: 10.1021/acschembio.7b00711
Kimberly E. Anderson ₁ , Milton To ₁ , James A. Olzmann ₁ , Daniel K. Nomura ₁

Affiliation

Covalent ligand discovery is a promising strategy to develop small-molecule effectors against therapeutic targets. Recent studies have shown that dichlorotriazines are promising reactive scaffolds that preferentially react with lysines. Here, we have synthesized a series of dichlorotriazine-based covalent ligands and have screened this library to reveal small molecules that impair triple-negative breast cancer cell survival. Upon identifying a lead hit from this screen KEA1-97, we used activity-based protein profiling (ABPP)-based chemoproteomic platforms to identify that this compound targets lysine 72 of thioredoxin—a site previously shown to be important in protein interactions with caspase 3 to inhibit caspase 3 activity and suppress apoptosis. We show that KEA1-97 disrupts the interaction of thioredoxin with caspase 3, activates caspases, and induces apoptosis without affecting thioredoxin activity. Moreover, KEA1-97 impairs in vivo breast tumor xenograft growth. Our study showcases how the screening of covalent ligands can be coupled with ABPP platforms to identify unique anticancer lead and target pairs.

中文翻译：

化学蛋白质组学启用的共价配体筛选揭示了损害乳腺癌致病性的硫氧还蛋白-胱天蛋白酶3相互作用破坏者。

共价配体的发现是开发针对治疗靶标的小分子效应子的有前途的策略。最近的研究表明，二氯三嗪是有前景的反应性支架，可以优先与赖氨酸反应。在这里，我们合成了一系列基于二氯三嗪的共价配体，并筛选了该文库以揭示损害三阴性乳腺癌细胞存活的小分子。在此屏幕KEA1-97上确定了潜在客户后，我们使用了基于活性的蛋白谱（ABPP）的化学旋转平台，以鉴定该化合物靶向硫氧还蛋白的赖氨酸72-以前显示的一个位点在与caspase 3的蛋白质相互作用中很重要抑制caspase 3活性并抑制细胞凋亡。我们显示KEA1-97破坏了硫氧还蛋白与caspase 3的相互作用，激活了半胱氨酸蛋白酶，并诱导细胞凋亡而不影响硫氧还蛋白的活性。而且，KEA1-97受损体内乳腺癌异种移植物的生长。我们的研究展示了如何将共价配体的筛选与ABPP平台结合使用，以识别独特的抗癌先导和靶标对。

更新日期：2017-09-13

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11