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Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors.

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机构： [1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center,West China Hospital of Sichuan University, Chengdu, 610041, China [2] Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education & State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, Guizhou, China [3]College of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China [4] Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610052, China

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关键词： PI3K/mTOR Structural optimization Dual inhibitor Cancer treatment

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PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate. Copyright © 2019. Published by Elsevier Masson SAS.

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出版当年[2019]版：

大类 | 1 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

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第一作者机构： [1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center,West China Hospital of Sichuan University, Chengdu, 610041, China

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