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Design, synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors
Author(s) -
Yang Xiuyan,
Deng Meng,
Zhang Xi,
Wang Yi,
Song Kun,
Cong Ruan,
Meng Linghua,
Zhang Jian
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13425
Subject(s) - pi3k/akt/mtor pathway , phosphatidylinositol , pyrimidine , kinase , chemistry , protein kinase b , in vivo , enzyme , biochemistry , cell growth , signal transduction , biology , microbiology and biotechnology
A series of thieno[3,2‐d]pyrimidine derivatives as phosphatidylinositol 3‐kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21 . Determination of a co‐crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.