Review Article

聚异丙二烯酰半steinyl Amide抑制剂:一种控制癌症过度活跃生长信号的新方法

卷 28, 期 18, 2021

发表于: 11 November, 2020

页: [3476 - 3489] 页: 14

弟呕挨: 10.2174/0929867327666201111140825

open access plus

摘要

单体g蛋白信号通路的异常激活导致了一些最具侵袭性的癌症。抑制这些过度活动一直是获得靶向治疗的重点。聚异戊二烯化甲基化蛋白甲基酯酶(PMPMEase)在各种癌症中过表达。它的抑制作用诱导了含有构成活性K-Ras蛋白的癌细胞的死亡。此外,由K-Ras上游因子驱动的癌细胞活力,如过表达的生长因子及其受体或突变激活的受体,也容易受到PMPMEase的抑制。因此,设计了聚异戊二烯酰半胱氨酸酰胺抑制剂(PCAIs),以靶向涉及g蛋白的过度活跃信号通路的癌症。然而,pcai是PMPMEase较差的抑制剂,Ki值从3.7到20 μM不等。另一方面,在EC50值为1 ~ 3 μM时,抑制K-Ras突变细胞的活力、增殖和集落形成,诱导细胞凋亡,抑制细胞迁移和侵袭。在亚微摩尔浓度下,通过破坏肌动蛋白丝的组织,HUVEC管的形成被抑制。在分子水平上,PCAIs为2 ~ 5 μM贫G蛋白单体,如K-Ras, RhoA, Cdc42和Rac1。PCAI也消耗参与肌动蛋白组织的vinculin和fasin,同时破坏vinculin在这个过程中的点状突起。这些研究证明了一种多异丙烯化依赖的机制,该机制解释了观察到的PCAIs抑制促进肿瘤生长和转移的增殖、侵袭和血管生成过程。

关键词: 聚异戊二烯酰半steinyl酰胺抑制剂 (PCAIs), K-Ras

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