2. Academic Validation
  3. Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors

Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors

  • Bioorg Med Chem. 2018 Feb 1;26(3):637-646. doi: 10.1016/j.bmc.2017.12.025.
Songwen Lin 1,  Chunyang Wang 2,  Ming Ji 2,  Deyu Wu 1,  Yuanhao Lv 2,  Li Sheng 3,  Fangbin Han 4,  Yi Dong 1,  Kehui Zhang 1,  Yakun Yang 3,  Yan Li 3,  Xiaoguang Chen 5,  Heng Xu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 4 PKUCare Pharmaceutical R&D Center, Beijing 102206, China.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: chxg@imm.ac.cn.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: xuheng@imm.ac.cn.
PMID: 29305298 DOI: 10.1016/j.bmc.2017.12.025
Abstract

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.

Keywords

Acetylation; Anti-tumor activities; Phosphoinositide 3-kinase inhibitors; Thienopyrimidine.

Figures