癌症治疗新方法：可开发出降解“无成药性”癌症蛋白的化合物

资讯作者：Weill Cornell Medical College

编辑翻译：奇奇

本文献刊登在著名期刊《科学转化医学》杂志上，研究人员开发出了一种能够降解癌症蛋白分子的化合物，该技术为研究其他“无成药性”的癌症蛋白提供了新思路，也为未来癌症治疗提供了新的方法。

印第安纳大学医学院的研究人员开发了一种化合物，该化合物可以降解促进癌症的蛋白分子SUMO1。发表在《科学转化医学》杂志上的论文中，该小组描述了他们试图为一种被认为无成药性的癌症的相关蛋白寻找降解剂。

图片来源：印第安纳大学医学院。图示为靶向分子与“无成药性”癌症蛋白的相关性

先前的研究表明，有一些蛋白质可以改变癌症蛋白质，帮助癌症的形成和扩散，但这些蛋白质被认为无成药性，这意味着似乎可能无法开发出一种阻止其作用的药物。此类蛋白质被认为具有化学挑战性。SUMO1就是这样的一种蛋白质。2014年，人们就发现它通过促进肿瘤生长来驱动某些癌症的细胞周期。它是通过附着在其他致癌蛋白质上实现的，这也是印第安纳州研究团队的工作重点。

为了找到一种可能降解SUMO1的药物，研究人员筛选了与蛋白质降解相关的1596种化合物的药物数据库。他们发现了一种叫做CPD1的分子，似乎是一个研究候选对象。在了解了它的特性之后，研究人员开发了一种新的先导化合物HB007。研究人员在真实环境中测试了这种新蛋白质。在小鼠模型中，他们发现给予这种蛋白质可以抑制乳腺癌、肺癌和结肠癌的发展。进一步的试验还表明，与对照组相比，这种蛋白质提高了小鼠模型的存活率。这些研究发现强调了类似SUMO1这样的蛋白质在促进肿瘤生长方面的重要性，以及为什么需要更多的研究来找到对抗它们的方法。

研究人员表示，他们的工作可能会引领对抗人类癌症的新方法。他们还表示，他们的工作可以作为其他科学家研究“不成药性”癌症蛋白质降解物方法的模板。

英文原文

Small Molecule Compound Developed That Can DegradeThe Cancer Promoting Protein SUMO1

A team of researchers working at the IndianaUniversity School of Medicine, has developed a compound that can degrade thecancer-promoting protein SUMO1. In their paper published in the journal ScienceTranslational Medicine, the group describes their work in attempting to find adegrader for what has been described as an undruggable cancer-related protein.

Prior research has shown that there are someproteins that change cancer proteins in ways that help it form and spread, butwhich are considered to be undruggable, meaning that it appears unlikely that adrug could be developed that would prevent it from doing its job. Such proteinsare considered to be chemically challenging. SUMO1 is one such protein. In 2014it was found to drive the cell cycle for certain cancers by promoting tumor growth.It does so by attaching to other cancer-forming proteins, and it was the focusof the work by the team in Indiana.

To find a drug that might degrade SUMO1, theresearchers screened a drug library of data regarding 1,596 compounds relatedto protein degradation. They found a molecule called CPD1 that appeared to be alikely candidate for study. After learning more about its characteristics, theresearchers developed a new lead compound called HB007. The researchers testedthe new protein under real-world conditions. In mouse models, they foundadministration of the protein suppressed the development of breast, lung andcolon tumors. Further testing also showed that the protein increased survivalrates in mouse models compared to control groups. The findings highlight theimportance of proteins like SUMO1 in promoting tumor growth, and why moreresearch is required to find ways to counteract them.

The researchers suggest that their work couldlead to new ways to fight cancer in humans. They also suggest that their workcould be used as a template for other scientists seeking ways of dealing with'undruggable' protein degraders.

参考文献

Anita C. Bellail et al, Ubiquitination anddegradation of SUMO1 by small-molecule degraders extends survival of mice withpatient-derived tumors, Science Translational Medicine (2021). 

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