2. Academic Validation
  3. Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment

Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment

  • J Med Chem. 2018 Jul 26;61(14):6087-6109. doi: 10.1021/acs.jmedchem.8b00416.
Songwen Lin 1 2,  Chunyang Wang 1,  Ming Ji 1,  Deyu Wu 1 2,  Yuanhao Lv 1,  Kehui Zhang 1 2,  Yi Dong 1 2,  Jing Jin 1,  Jiajing Chen 1 2,  Jingbo Zhang 1 2,  Li Sheng 3,  Yan Li 3,  Xiaoguang Chen 1,  Heng Xu 1 2
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.
  • 2 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, 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.
PMID: 29927604 DOI: 10.1021/acs.jmedchem.8b00416
Abstract

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in Cancer, spurring intensive efforts to develop new Cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.

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