期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 209, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112913
关键词
PI3K; Pyrrolo[2,1-f][1,2,4]triazine; Anti-cancer; Target therapy
资金
- National Natural Science Foundation of China [90713034, 81703365]
- Institutes for Drug Discovery and Development, Chinese Academy of Sciences [CASIMM0120185009]
- State Key Laboratory of Drug Research Program [SIMM1705KF-15]
- Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020111, XDA12050407]
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program [2018ZX09711002-011-014]
The PI3Ks pathway is commonly dysregulated in human cancers, making it a promising target for anti-cancer drugs. Compound 37 (CYH33) was identified as a selective PI3Ka inhibitor with potential anti-cancer properties, inhibiting phosphorylation of AKT to modulate the PI3K/AKT/mTOR pathway in human cancer cells. Evaluation in vivo against SKOV-3 xenograft models demonstrated dose-dependent antitumor efficacy.
In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Ka inhibitor (IC50 = 5.9 nM, beta/alpha, delta/alpha,gamma/alpha= 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved. (C) 2020 Elsevier Masson SAS. All rights reserved.
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