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

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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Pan-KRAS destruction with a single PROTAC

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来源期刊

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

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