Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR

  • ACS Med Chem Lett. 2018 Feb 27;9(3):256-261. doi: 10.1021/acsmedchemlett.8b00002.
Tao Yu  1 ,  Ning Li  1 ,  Chengde Wu  1 ,  Amy Guan  1 ,  Yi Li  1 ,  Zhengang Peng  1 ,  Miao He  1 ,  Jie Li  1 ,  Zhen Gong  1 ,  Lei Huang  1 ,  Bo Gao  1 ,  Dongling Hao  1 ,  Jikui Sun  1 ,  Yan Pan  1 ,  Liang Shen  1 ,  Chichung Chan  1 ,  Xiulian Lu  2 ,  Hongyu Yuan  2 ,  Yongguo Li  2 ,  Jian Li  1 ,  Shuhui Chen  1
Affiliations
  • 1. Domestic Discovery Service Unit, WuXi AppTec (Shanghai) Co. Ltd., 288 FuteZhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 2. Cisen Pharmaceutical Co. Ltd., Tongji Sci-tech Industrial Park, High-tech Industrial Development Zone, Jining, Shandong 272073, China.
PMID: 29541370 DOI: 10.1021/acsmedchemlett.8b00002
Abstract

The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70S6K phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.

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