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

Songwen Lin; Chunyang Wang; Ming Ji; Deyu Wu; Yuanhao Lv; Li Sheng; Fangbin Han; Yi Dong; Kehui Zhang; Yakun Yang; Yan Li; Xiaoguang Chen; Heng Xu

doi:10.1016/j.bmc.2017.12.025

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. Epub 2017 Dec 23.

Authors

Songwen Lin¹, Chunyang Wang², Ming Ji², Deyu Wu¹, Yuanhao Lv², Li Sheng³, Fangbin Han⁴, Yi Dong¹, Kehui Zhang¹, Yakun Yang³, Yan Li³, Xiaoguang Chen⁵, Heng Xu⁶

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
Half-Life
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Microsomes, Liver / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Structure-Activity Relationship
Transplantation, Heterologous

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyrimidines
thienopyrimidine