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首页> 外文期刊>Molecular & cellular proteomics: MCP >Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation
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Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation

机译：针对泛素化和降解的促癌蛋白靶标的开发

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The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment of human diseases. However, many of these proteins are from functional classes that have never been validated as viable candidates for the development of small molecule inhibitors. Thus, to exploit fully the potential of the Human Genome Project to advance human medicine, there is a need to develop generic methods of inhibiting protein activity that do not rely on the target protein’s function. We previously demonstrated that a normally stable protein, methionine aminopeptidase-2 or MetAP-2, could be artificially targeted to an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex for ubiquitination and degradation through a chimeric bridging molecule or Protac (proteolysis targeting chimeric molecule). This Protac consisted of an SCF~(β-TRCP)-binding phosphopeptide derived from IκBα linked to ovalicin, which covalently binds MetAP-2. In this study, we employed this approach to target two different proteins, the estrogen (ER) and androgen (AR) receptors, which have been implicated in the progression of breast and prostate cancer, respectively. We show here that an estradiol-based Protac can enforce the ubiquitination and degradation of the isoform of ER in vitro, and a dihydroxytestosterone-based Protac introduced into cells promotes the rapid disappearance of AR in a proteasome-dependent manner. Future improvements to this technology may yield a general approach to treat a number of human diseases, including cancer.
机译：蛋白质组包含数百种蛋白质，从理论上讲，它们可以成为治疗人类疾病的极佳治疗靶标。但是，这些蛋白质中有许多来自功能类别，这些功能类别从未被证实是开发小分子抑制剂的可行候选者。因此，为了充分利用人类基因组计划发展人类医学的潜力，需要开发不依赖目标蛋白质功能的通用蛋白质抑制方法。我们以前证明了正常稳定的蛋白质蛋氨酸氨基肽酶2或MetAP-2可以人为地靶向Skp1-Cullin-F-box（SCF）泛素连接酶复合物，以通过嵌合桥联分子或Protac进行泛素化和降解（蛋白水解靶向嵌合分子）。该Protac由衍生自与卵磷脂连接的IκBα的SCF〜（β-TRCP）结合磷酸肽组成，该卵磷脂共价结合MetAP-2。在这项研究中，我们采用这种方法来靶向两种不同的蛋白质，雌激素（ER）和雄激素（AR）受体，它们分别与乳腺癌和前列腺癌的发展有关。我们在这里显示，基于雌二醇的Protac可以在体外增强ER的同种型的泛素化和降解，而引入细胞中的基于二羟基睾丸酮的Protac可以以蛋白酶体依赖性的方式促进AR的快速消失。对该技术的未来改进可能会产生一种治疗许多人类疾病（包括癌症）的通用方法。

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