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

中文翻译：

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β-咔啉衍生物 Z86 通过直接靶向 PI3K 减弱结直肠癌细胞增殖和迁移

磷酸肌醇 3-激酶 (PI3K) 是广泛参与细胞增殖、转移和分化的脂质激酶。PI3K/Akt/mTOR 信号传导的组成性激活在结直肠癌 (CRC) 中得到了充分证实。在本研究中，我们鉴定出 9-乙基-1-(萘-1-基)-9 H-吡啶并[3,4-b]吲哚-3-甲酸异丙酯 (Z86)，作为一种新型 PI3Kα 抑制剂，IC ₅₀值为 4.28 µM。通过 DARTS 和 CETSA 测定进一步证实了 Z86 与 PI3Kα 的结合。免疫荧光分析和蛋白质印迹数据表明，Z86 有效减弱 PI3K/AKT 通路。Z86 通过 G0/G1 周期阻滞而不是诱导细胞凋亡来显着抑制 CRC 的增殖。此外，Z86也缓解了CRC的迁移。本研究不仅确定了Z86作为一种新型PI3Kα抑制剂，对PI3K介导的CRC生长和迁移具有有效的抑制作用，而且阐明了Z86抑制Wnt信号通路的合理分子机制。

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