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

Guoyi Yan; Chunlan Pu; Suke Lan; Xinxin Zhong; Meng Zhou; Xueyan Hou; Jie Yang; Huifang Shan; Lifeng Zhao; Rui Li

doi:10.1016/j.ejmech.2019.06.021

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. Epub 2019 Jun 13.

Authors

Guoyi Yan¹, Chunlan Pu¹, Suke Lan¹, Xinxin Zhong¹, Meng Zhou², Xueyan Hou³, Jie Yang¹, Huifang Shan¹, Lifeng Zhao⁴, Rui Li⁵

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: lifengzhao@scu.edu.cn.
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: lirui@scu.edu.cn.

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.

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzoxazines / administration & dosage
Benzoxazines / chemistry
Benzoxazines / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
Benzoxazines
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
MTOR protein, human
TOR Serine-Threonine Kinases