Double Swords in One: Novel Selective PI3K/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-04-28 DOI:10.1021/acs.jmedchem.4c03169

Juan Cen, Ping Lu, Chenwei Wang, Jing Wu, Xiaojiao Hu, Han Zhao, Mengyu Li, Mingkai Luo, Shizhen Zhao, Xiaohui Li, Shaofeng Duan

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引用次数: 0

Abstract

The p110β isoform of the PI3 kinase (PI3K) family plays a key role in tumorigenesis and PTEN loss-driven multidrug resistance (MDR). Herein, we describe the design, synthesis, and structure–activity relationship studies of a series of small-molecule PI3K/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3K/110β with VHL ligands. Among them, J-6 and J-9 exhibited rapid and efficient degradation ability for the target proteins in MDR cells. Meanwhile, the expression and activity of P-glycoprotein were significantly inhibited, leading to a strong synergistic antitumor effect with adriamycin or cisplatin. Further studies confirmed that the two degraders can induce endoplasmic reticulum stress-mediated mitochondrial apoptosis by the AKT/Bcl-2 inhibition-mediated PERK/CHOP-unfolded protein reaction. In vivo studies also verified that the two degraders inhibited the growth of MCF-7/ADM xenograft tumors with high safety. Hence, this study and further optimization of these PI3K/110β PROTAC degraders have broad prospects for the development of new cancer therapies.

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双剑合一：通过激活ERS和抑制P-gp治疗多药耐药癌症的新型选择性PI3K/110β PROTAC降解剂

PI3K家族的p110β亚型在肿瘤发生和PTEN损失驱动的多药耐药（MDR）中起关键作用。本文通过将PI3K/110β选择性抑制剂TGX221与VHL配体结合，设计、合成了一系列小分子PI3K/110β PROTACs降解物，并进行了结构-活性关系研究。其中，J-6和J-9在MDR细胞中对靶蛋白表现出快速有效的降解能力。同时p -糖蛋白的表达和活性被显著抑制，与阿霉素、顺铂具有较强的协同抗肿瘤作用。进一步研究证实，这两种降解物可通过AKT/Bcl-2抑制介导的PERK/ chop -未折叠蛋白反应诱导内质网应激介导的线粒体凋亡。体内研究也证实了这两种降解剂对MCF-7/ADM异种移植物肿瘤生长的抑制作用，且具有较高的安全性。因此，本研究和进一步优化这些PI3K/110β PROTAC降解物在开发新的癌症治疗方法方面具有广阔的前景。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.