β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

IF 4.8 3区化学 Q1 CHEMISTRY, MEDICINAL

Natural Products and Bioprospecting Pub Date : 2024-01-03 DOI:10.1007/s13659-023-00422-y

Shiyun Nie, Lizhong Chang, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong, Yan Li

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Abstract

Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC₅₀ value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.

Graphical Abstract

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β-咔啉衍生物 Z86 通过直接靶向 PI3K 抑制结直肠癌细胞的增殖和迁移

磷脂激酶（PI3K）是一种脂质激酶，广泛参与细胞增殖、转移和分化。在结直肠癌（CRC）中，PI3K/Akt/mTOR 信号的连续激活已得到证实。在这项研究中，我们发现 9-乙基-1-（萘-1-基）-9 H-吡啶并[3,4-b]吲哚-3-羧酸异丙酯（Z86）是一种新型 PI3Kα 抑制剂，其 IC50 值为 4.28 µM。Z86 与 PI3Kα 的结合通过 DARTS 和 CETSA 试验得到了进一步证实。免疫荧光分析和 Western 印迹数据表明，Z86 能有效抑制 PI3K/AKT 通路。Z86 通过 G0/G1 周期阻滞而非诱导凋亡，显著抑制了 CRC 的增殖。此外，Z86 还能缓解 CRC 的迁移。本研究不仅发现了Z86是一种新型的PI3Kα抑制剂，对PI3K介导的CRCs生长和迁移具有强效抑制作用，而且阐明了Z86在Wnt信号通路抑制中的合理分子机制。

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来源期刊

Natural Products and Bioprospecting CHEMISTRY, MEDICINAL-

CiteScore

8.30

自引率

2.10%

发文量

审稿时长

13 weeks

期刊介绍： Natural Products and Bioprospecting serves as an international forum for essential research on natural products and focuses on, but is not limited to, the following aspects: Natural products: isolation and structure elucidation Natural products: synthesis Biological evaluation of biologically active natural products Bioorganic and medicinal chemistry Biosynthesis and microbiological transformation Fermentation and plant tissue cultures Bioprospecting of natural products from natural resources All research articles published in this journal have undergone rigorous peer review. In addition to original research articles, Natural Products and Bioprospecting publishes reviews and short communications, aiming to rapidly disseminate the research results of timely interest, and comprehensive reviews of emerging topics in all the areas of natural products. It is also an open access journal, which provides free access to its articles to anyone, anywhere.