Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

IF 5.4 2区 医学 Q1 CHEMISTRY, MEDICINAL Expert Opinion on Therapeutic Patents Pub Date : 2024-03-01 Epub Date: 2024-04-09 DOI:10.1080/13543776.2024.2338100
Dima A Sabbah, Rima Hajjo, Sanaa K Bardaweel, Haizhen A Zhong
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Abstract

Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed.

Area covered: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023.

Expert opinion: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

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在抗癌研究中靶向 PI3K/AKT 信号通路:抑制剂设计和临床试验的最新进展(2020-2023 年)。
导言:近年来,针对磷脂酰肌醇 3- 激酶/蛋白激酶-B(PI3K/AKT)信号通路的药物设计和开发取得了巨大成就。PI3K和AKT的近邻蛋白-蛋白相互作用网络显示了这些靶蛋白之间的相互作用,可用于药物发现。在这篇综述中,我们讨论了过去三年中 PI3K/AKT 抑制剂的药物设计和临床开发。我们详细回顾了根据靶蛋白分类的 35 种针对这些蛋白的抑制剂的结构、选择性、疗效和联合疗法。我们还讨论了克服耐药性和减少毒性的方法。还讨论了开发 PI3K 和 AKT 抑制剂的联合疗法和 PROTAC 的未来研究方向:本综述涵盖 2020 年至 2023 年间发表的有关 PI3K 和 AKT 抑制剂的临床试验报告和专利文献:为解决PI3K和AKT抑制剂的耐药性和药物毒性问题,设计和开发亚型选择性PI3K抑制剂或亚型选择性AKT1抑制剂以最大限度地降低毒性,或开发可形成共价键的异构药物是非常可取的。开发 PI3Kα 或 AKT 的 PROTACs 有助于减少脱靶毒性。
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来源期刊
CiteScore
12.10
自引率
1.50%
发文量
50
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Therapeutic Patents (ISSN 1354-3776 [print], 1744-7674 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on recent pharmaceutical patent claims, providing expert opinion the scope for future development, in the context of the scientific literature. The Editors welcome: Reviews covering recent patent claims on compounds or applications with therapeutic potential, including biotherapeutics and small-molecule agents with specific molecular targets; and patenting trends in a particular therapeutic area Patent Evaluations examining the aims and chemical and biological claims of individual patents Perspectives on issues relating to intellectual property The audience consists of scientists, managers and decision-makers in the pharmaceutical industry and others closely involved in R&D Sample our Bioscience journals, sign in here to start your access, Latest two full volumes FREE to you for 14 days.
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