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

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.

SUBMITTER: Yu T

PROVIDER: S-EPMC5846042 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Yu Tao T Li Ning N Wu Chengde C Guan Amy A Li Yi Y Peng Zhengang Z He Miao M Li Jie J Gong Zhen Z Huang Lei L Gao Bo B Hao Dongling D Sun Jikui J Pan Yan Y Shen Liang L Chan Chichung C Lu Xiulian X Yuan Hongyu H Li Yongguo Y Li Jian J Chen Shuhui S

ACS medicinal chemistry letters 20180227 3

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. ...[more]

PMID: 29541370

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