title: Discovery of a Novel Series of Thienopyrimidine as Highly Potent and Selective PI3K Inhibitors.
abstract: 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.
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Fangbin
authors.initials: F
authors.lastname: Han
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Songwen
authors.initials: S
authors.lastname: Lin
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Xiujie
authors.initials: X
authors.lastname: Liu
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tao
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Deng
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Chongqin
authors.initials: C
authors.lastname: Yi
authors.affiliation: PKUCare Pharmaceutical R&D Center, A106-109, Biotech Innovation Works , No. 29 Life Science Park Road, Changping District, Beijing 102206, P. R. China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
keywords: dual inhibitors; mammalian target of rapamycin; phosphoinositide 3-kinase; selective PI3K inhibitors; thienopyrimidines