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β-咔啉衍生物Z86通过直接靶向PI3K来减弱结肠直肠癌细胞的增殖和迁移。

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

作者信息

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

机构信息

Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.

出版信息

Nat Prod Bioprospect. 2024 Jan 3;14(1):3. doi: 10.1007/s13659-023-00422-y.

DOI:10.1007/s13659-023-00422-y
PMID:38169019
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10761647/
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 IC 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.

摘要

磷酸肌醇-3激酶（PI3Ks）是一类脂质激酶，广泛参与细胞增殖、转移和分化过程。PI3K/Akt/mTOR信号通路的组成性激活在结直肠癌（CRCs）中已得到充分证实。在本研究中，我们鉴定出9-乙基-1-（萘-1-基）-9H-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IC值为4.28 µM。通过DARTS和CETSA实验进一步证实了Z86与PI3Kα的结合。免疫荧光分析和蛋白质印迹数据表明，Z86能有效减弱PI3K/AKT信号通路。Z86通过使细胞周期停滞在G0/G1期而非诱导凋亡，显著抑制了结直肠癌的增殖。此外，Z86还能抑制结直肠癌的迁移。本研究不仅鉴定出Z86是一种对PI3K介导的结直肠癌生长和迁移具有高效抑制作用的新型PI3Kα抑制剂，还阐明了Z86在Wnt信号通路抑制中的合理分子机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/1ecbee8dc036/13659_2023_422_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/403673bba948/13659_2023_422_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/e16018caefd2/13659_2023_422_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/75de75050bb0/13659_2023_422_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/1ecbee8dc036/13659_2023_422_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/403673bba948/13659_2023_422_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/e16018caefd2/13659_2023_422_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/75de75050bb0/13659_2023_422_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b175/10761647/1ecbee8dc036/13659_2023_422_Fig4_HTML.jpg

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