使用单个 PROTAC 销毁泛 KRAS

IF 33.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Nature biotechnology Pub Date : 2024-10-14 DOI:10.1038/s41587-024-02445-3
Iris Marchal
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引用次数: 0

摘要

大多数针对致癌 Kirsten 大鼠肉瘤病毒(KRAS)突变体的小分子药物都依赖于与变体特异性氨基酸残基的相互作用。然而,人类癌症中普遍存在多种 KRAS 突变,无法药用的变体给 KRAS 突变肿瘤的临床治疗带来了巨大挑战。在发表于《科学》(Science)的一篇论文中,Popow 等人通过设计一种蛋白水解靶向嵌合体(PROTAC)来解决这一问题,这种嵌合体能降解范围广泛的 KRAS 变异体。研究人员将以前使用过的一种配体与一种连接体以及 Von Hippel-Lindau (VHL) E3 连接酶的结合基团结合在一起。先导化合物的优化提高了稳定性和与细胞内 VHL 的结合,从而产生了一种能在体外有效降解 17 种 KRAS 突变变体中 13 种的 PROTAC。无偏质谱蛋白质组学显示,50%的蛋白质被降解,仅检测到KRAS,这表明PROTAC对KRAS具有高度选择性。Pan-KRAS 降解抑制了致癌 MAPK 信号传导,并抑制了由不同 KRAS 突变体驱动的癌细胞系的增殖。降解 KRAS 的效果是抑制 KRAS 效果的 10 倍以上。一种名为 ACB13 的体内优化化合物可使小鼠的 KRAS 突变肿瘤消退。
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Pan-KRAS destruction with a single PROTAC
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来源期刊
Nature biotechnology
Nature biotechnology 工程技术-生物工程与应用微生物
CiteScore
63.00
自引率
1.70%
发文量
382
审稿时长
3 months
期刊介绍: Nature Biotechnology is a monthly journal that focuses on the science and business of biotechnology. It covers a wide range of topics including technology/methodology advancements in the biological, biomedical, agricultural, and environmental sciences. The journal also explores the commercial, political, ethical, legal, and societal aspects of this research. The journal serves researchers by providing peer-reviewed research papers in the field of biotechnology. It also serves the business community by delivering news about research developments. This approach ensures that both the scientific and business communities are well-informed and able to stay up-to-date on the latest advancements and opportunities in the field. Some key areas of interest in which the journal actively seeks research papers include molecular engineering of nucleic acids and proteins, molecular therapy, large-scale biology, computational biology, regenerative medicine, imaging technology, analytical biotechnology, applied immunology, food and agricultural biotechnology, and environmental biotechnology. In summary, Nature Biotechnology is a comprehensive journal that covers both the scientific and business aspects of biotechnology. It strives to provide researchers with valuable research papers and news while also delivering important scientific advancements to the business community.
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