2. Academic Validation
  3. Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines

Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines

  • ACS Med Chem Lett. 2018 Jun 25;9(7):719-724. doi: 10.1021/acsmedchemlett.8b00167.
Sida Shen 1,  Xiangyu He 1,  Zheng Yang 1,  Liang Zhang 1,  Yingtao Liu 1,  Zhiyuan Zhang 1,  Weiwei Wang 1,  Wei Liu 1,  Yufeng Li 1,  Dong Huang 1,  Kai Sun 1,  Xiaojing Ni 1,  Xu Yang 1,  Xinxin Chu 1,  Yumin Cui 1,  Qiang Lv 1,  Jiong Lan 1,  Fusheng Zhou 1
Affiliations

Affiliation

  • 1 Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., No. 8, 67 Libing Road, Shanghai 201203, China.
PMID: 30034607 DOI: 10.1021/acsmedchemlett.8b00167
Abstract

The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR Inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of Akt phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of Cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

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