Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept

被引：31

作者：

Hudson, Liam ^{[1
]}

Mui, James ^{[1
]}

Vazquez, Santiago ^{[3
,4
]}

Carvalho, Diana M. ^{[1
]}

Williams, Eleanor ^{[2
]}

Jones, Chris ^{[1
]}

Bullock, Alex N. ^{[2
]}

Hoelder, Swen ^{[1
]}

机构：

[1] Inst Canc Res, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England

[2] Univ Oxford, Struct Genom Consortium, Old Rd Campus,Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England

[3] Univ Barcelona, Fac Farmacia & Ciencies Alimentacio, Unitat Associada CSIC, Lab Quim Farmaceut, Av Joan XXIII S-N, E-08028 Barcelona, Spain

[4] Univ Barcelona, Inst Biomed IBUB, Av Joan XXIII S-N, E-08028 Barcelona, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 16期

基金：

英国惠康基金; 加拿大创新基金会; 巴西圣保罗研究基金会;

关键词：

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; TGF-BETA; DISCOVERY; SERIES;

D O I：

10.1021/acs.jmedchem.8b00782

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationship and crystallo-graphic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.

引用

页码：7261 / 7272

页数：12

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