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A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures of known anti-cancer agents, namely gedatolisib and alpelisib. All the target compounds were screened for inhibitory activity against PI3Kα and mTOR kinases. Notably, most analogs exhibited IC50 in the nanomolar range. Investigation of the isozyme selectivity indicated that the compounds exhibited remarkable inhibitory activity against PI3Kδ, especially compound 19f showed an IC50 value of 2.3 nM for PI3Kδ and moderate δ-isozyme selectivity over other class I PI3K isoforms and mTOR (with IC50 values of 14.6, 34.0, 849.0 and 15.4 nM for PI3Kα, β, γ and mTOR, respectively). An in vitro MTT assay was conducted to assess the antiproliferative and cytotoxic effects of the prepared analogs. It was revealed that the compounds displayed significant inhibitory activities against the HCT116 human colon cancer cell line. Compound 19i showed 4.7-fold higher potency than the positive control gedatolisib (0.3 vs. 1.4 μM, IC50 values). Phosphoblot studies demonstrated that 19c and 19i could significantly suppress the PI3K/Akt/mTOR signaling pathway at 10 μM. Moreover, analogs 19b, 19c and 19i displayed better stability in artificial gastric fluids than gedatolisib, while 19i was indicated not very stable in rat liver microsomes, and may occur phase I metabolic transformations. Copyright © 2020 Elsevier Masson SAS. All rights reserved.


Ting-Ting Wu, Qing-Qing Guo, Zi-Li Chen, Li-Li Wang, Yao Du, Rui Chen, Yuan-Hu Mao, Sheng-Gang Yang, Jing Huang, Jian-Ta Wang, Ling Wang, Lei Tang, Ji-Quan Zhang. Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors. European journal of medicinal chemistry. 2020 Oct 15;204:112637

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PMID: 32717477

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