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
  • 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.

Products