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EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC., (Copyright © 2020. Published by Elsevier Ltd.)

Phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, autophagy and apoptosis. Class I PI3K is frequently mutated and overexpressed in a lot of human cancers and PI3K was considered as a target for therapeutic treatment of cancer. In this study, we designed and synthesized a series of 1,6-disubstituted-1H-benzo[d]imidazoles derivatives and evaluated their anticancer activity and the compound 8i was identified as a lead compound. Compound 8i with the most potent antiproliferative activity was selected for further biological mechanism. The PI3K kinase assay have shown potent efficiency against four subtypes of PI3K with an IC 50 of 0.5-1.9 nM. Molecular docking showed a possible formation of H-bonding with essential amino acid residues. Meanwhile, western blot assay indicated that 8i inhibited cell proliferation via suppression of PI3K kinase activity and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 8i could inhibit the migration and invasion ability of HCT116 cells and could induce apoptosis of HCT116 cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC 50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents., (Copyright © 2019 Elsevier Ltd. All rights reserved.)