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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 PI3K? 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.

SUBMITTER: Han F

PROVIDER: S-EPMC4394348 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Han Fangbin F Lin Songwen S Liu Peng P Liu Xiujie X Tao Jing J Deng Xiaobing X Yi Chongqin C Xu Heng H

ACS medicinal chemistry letters 20150311 4

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 profile ...[more]

PMID: 25893045

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