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科学家发现一种用于心脏保护和神经再生的小分子PI3Kα激活剂
作者:小柯机器人 发布时间:2023/5/31 16:29:48

英国伦敦大学学院Bart Vanhaesebroeck小组发现一种用于心脏保护和神经再生的小分子PI3Kα激活剂。这一研究成果于2023年5月24日在线发表在国际学术期刊《自然》上。

研究人员报告了UCL-TRO-1938(简称1938)的发现,这是一种PI3Kα异构体的小分子激活剂,是生长因子信号的关键效应物。1938通过一种独特的机制,通过增强PI3Kα催化循环的多个步骤,异构激活PI3Kα,并引起PI3Kα结构的局部和整体构象变化。该化合物对PI3Kα的选择性高于其他PI3K异构体和多种蛋白和脂质激酶。在所有测试的啮齿动物和人类细胞中,它能暂时激活PI3K信号,导致细胞反应,如增殖和神经元外生长。在啮齿动物模型中,1938的急性治疗提供了对缺血再灌注损伤的心脏保护,并且在局部给药后,增强了神经压迫后的神经再生。

这项研究确定了一种直接探测PI3Kα信号通路的化学工具和一种调控PI3K活性的新方法,并扩大了通过短期激活这些酶来保护和再生组织的治疗潜力。这些发现说明了激活激酶以获得治疗效果的潜力,这是目前药物开发的一个基本未开发的领域。

据了解,通过产生直接激酶激活剂来利用激酶信号的潜在有益作用,仍然是药物开发中未被充分探索的领域。这也适用于PI3K信号通路,该通路已被抑制剂广泛地用于PI3K过度激活的情况,如癌症和免疫失调。

附:英文原文

Title: A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Author: Gong, Grace Q., Bilanges, Benoit, Allsop, Ben, Masson, Glenn R., Roberton, Victoria, Askwith, Trevor, Oxenford, Sally, Madsen, Ralitsa R., Conduit, Sarah E., Bellini, Dom, Fitzek, Martina, Collier, Matt, Najam, Osman, He, Zhenhe, Wahab, Ben, McLaughlin, Stephen H., Chan, A. W. Edith, Feierberg, Isabella, Madin, Andrew, Morelli, Daniele, Bhamra, Amandeep, Vinciauskaite, Vanesa, Anderson, Karen E., Surinova, Silvia, Pinotsis, Nikos, Lopez-Guadamillas, Elena, Wilcox, Matthew, Hooper, Alice, Patel, Chandni, Whitehead, Maria A., Bunney, Tom D., Stephens, Len R., Hawkins, Phillip T., Katan, Matilda, Yellon, Derek M., Davidson, Sean M., Smith, David M., Phillips, James B., Angell, Richard, Williams, Roger L., Vanhaesebroeck, Bart

Issue&Volume: 2023-05-24

Abstract: Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

DOI: 10.1038/s41586-023-05972-2

Source: https://www.nature.com/articles/s41586-023-05972-2

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html