Discovery of novel morpholino–quinoxalines as PI3Kα inhibitors by pharmacophore-based screening

Peng Wu; Yi Su; Xiaowen Liu; Jingying Yan; Yong Ye; Lei Zhang; Jianchao Xu; Shaoyu Weng; Yani Li; Tao Liu; Xiaowu Dong; Maotang Sun; Bo Yang; Qiaojun He; Yongzhou Hu

doi:10.1039/C2MD00255H

Discovery of novel morpholino–quinoxalines as PI3Kα inhibitors by pharmacophore-based screening†‡

Peng Wu,^a Yi Su,^b Xiaowen Liu,^b Jingying Yan,^a Yong Ye,^a Lei Zhang,^b Jianchao Xu,^a Shaoyu Weng,^a Yani Li,^a Tao Liu,^a Xiaowu Dong,^a Maotang Sun,^a Bo Yang,^b Qiaojun He^b and Yongzhou Hu*^a

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* Corresponding authors

^a ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

^b Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
E-mail: huyz@zju.edu.cn
Fax: +86 571 8820 8460
Tel: +086 571 8820 8460

Abstract

A pharmacophore model of PI3Kα inhibitors was built using the DiscoveryStudio 2.0 package. Pharmacophore-based screening (PBS) retrieved a series of novel morpholino–quinoxalines as PI3Kα inhibitors, as exemplified by 1a (PI3Kα IC₅₀: 0.44 μM). All target compounds showed good in vitro cytotoxicity against tested human cell lines. A pharmacophore mapping analysis and docking study indicated that both the morpholino group and the sulfonyl group contributed significantly to the potent PI3Kα inhibitory activity and cytotoxicity of the compounds.

MedChemComm

Discovery of novel morpholino–quinoxalines as PI3Kα inhibitors by pharmacophore-based screening†‡

Abstract

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Discovery of novel morpholino–quinoxalines as PI3Kα inhibitors by pharmacophore-based screening

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