Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
Int J Mol Sci. 2020 Sep 29;21(19):7198. doi: 10.3390/ijms21197198.
Signaling pathways regulated by the phosphoinositide 3-kinase (PI3K) enzymes have a well-established role in cancer development and progression. Over the past 30 years, the therapeutic potential of targeting this pathway has been well recognized, and this has led to the development of a multitude of drugs, some of which have progressed into clinical trials, with few of them currently approved for use in specific cancer settings. While many inhibitors compete with ATP, hence preventing the catalytic activity of the kinases directly, a deep understanding of the mechanisms of PI3K-dependent activation of its downstream effectors led to the development of additional strategies to prevent the initiation of this signaling pathway. This review summarizes previously published studies that led to the identification of inositol polyphosphates as promising parent molecules to design novel inhibitors of PI3K-dependent signals. We focus our attention on the inhibition of protein-membrane interactions mediated by binding of pleckstrin homology domains and phosphoinositides that we proposed 20 years ago as a novel therapeutic strategy.
磷酸肌醇 3-激酶（PI3K）酶调控的信号通路在癌症的发生和发展中具有明确的作用。在过去的 30 年中，靶向该通路的治疗潜力已得到充分认识，这导致了大量药物的开发，其中一些已进入临床试验阶段，目前只有少数药物在特定癌症治疗中获得批准。虽然许多抑制剂与 ATP 竞争，从而直接阻止激酶的催化活性，但对 PI3K 依赖性激活其下游效应物的机制的深入了解，导致了开发额外策略来防止该信号通路的启动。本文综述了先前的研究，这些研究导致了肌醇多磷酸盐作为设计新型 PI3K 依赖性信号抑制剂的有前途的母体分子的鉴定。我们将注意力集中在我们 20 年前提出的通过结合 pleckstrin 同源结构域和磷酸肌醇抑制由蛋白-膜相互作用介导的抑制上，这被提议作为一种新的治疗策略。
