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Discovery of a Novel Series of Thienopyrimidine as Highly Potent and Selective PI3K Inhibitors. 2015

Fangbin Han, and Songwen Lin, and Peng Liu, and Xiujie Liu, and Jing Tao, and Xiaobing Deng, and Chongqin Yi, and Heng Xu
PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.

Inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway provides a promising new approach for cancer therapy. Through a rational design, a novel series of thienopyrimidine was discovered as highly potent and selective PI3K inhibitors. These thienopyrimidine derivatives were demonstrated to bear nanomolar PI3Kα inhibitory potency with over 100-fold selectivity against mTOR kinase. The lead compounds 6g and 6k showed good developability profiles in cell-based proliferation and ADME assays. In this communication, their design, synthesis, structure-activity relationship, selectivity, and some developability properties are described.

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