Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors

被引：192

作者：

Hayakawa, Masahiko

Kaizawa, Hiroyuki

Moritomo, Hiroyuki

Koizumi, Tomonobu

Ohishi, Takahide

Okada, Minoru

Ohta, Mitsuaki

Tsukamoto, Shin-ichi

Parker, Peter

Workman, Paul

Waterfield, Mike

机构：

[1] Astellas Pharm Inc, Inst Drug Discovery Res, Tsuchiura, Ibaraki 3002698, Japan

[2] Canc Res UK London Res Inst, London WC2A 3PX, England

[3] Canc Res UK Ctr Canc Therapeut, Inst Canc Res, Sutton SN2 5NG, Surrey, England

[4] Ludwig Inst Canc Res, London W1W 7BS, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2006年 / 14卷 / 20期

关键词：

PI3; kinase; p110; alpha; inhibitor; cancer treatment;

D O I：

10.1016/j.bmc.2006.06.046

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of 4-morpholino-2-phenylquinazolines and related derivatives were prepared and evaluated as inhibitors of PI3 kinase p110 alpha. In this series, the thieno[3,2-d]pyrimidine derivative 15e showed the strongest inhibitory activity against p110 alpha, with an IC50 value of 2.0 nM, and inhibited proliferation of A375 melanoma cells with an IC50 value of 0.58 mu M. Moreover, 15e was found to be selective for p110 alpha over other PI3K isoforms and protein kinases, making it the first example of a selective PI3K p110 alpha inhibitor. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：6847 / 6858

页数：12

共 33 条

[31] Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents [J].