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

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

  • Eur J Med Chem. 2019 Sep 15;178:667-686. doi: 10.1016/j.ejmech.2019.06.021.
Guoyi Yan 1,  Chunlan Pu 1,  Suke Lan 1,  Xinxin Zhong 1,  Meng Zhou 2,  Xueyan Hou 3,  Jie Yang 1,  Huifang Shan 1,  Lifeng Zhao 4,  Rui Li 5
Affiliations

Affiliations

  • 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. Electronic address: [email protected].
  • 5 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 31228810 DOI: 10.1016/j.ejmech.2019.06.021
Abstract

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.

Keywords

Cancer treatment; Dual inhibitor; PI3K/mTOR; Structural optimization.

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