Structural Basis for Targeting the Folded P-Loop Conformation of c-MET

被引：18

作者：

Collie, Gavin W. ^{[1
]}

Michaelides, Iacovos N. ^{[1
]}

Embrey, Kevin ^{[1
]}

Stubbs, Christopher J. ^{[1
]}

Borjesson, Ulf ^{[2
]}

Dale, Ian L. ^{[1
]}

Snijder, Arjan ^{[2
]}

Barlind, Louise ^{[2
]}

Song, Kun ^{[3
]}

Khurana, Puneet ^{[1
]}

Phillips, Christopher ^{[1
]}

Storer, R. Ian ^{[1
]}

机构：

[1] AstraZeneca, Discovery Sci, R&D, Cambridge, England

[2] AstraZeneca, Discovery Sci, R&D, Gothenburg, Sweden

[3] AstraZeneca, Oncol, R&D, Boston, MA USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2021年 / 12卷 / 01期

关键词：

c-MET; kinase; X-ray crystallography; P-loop; small molecule inhibitor; ACQUIRED-RESISTANCE; KINASE; INHIBITORS; CRIZOTINIB; DESIGN; ABL;

D O I：

10.1021/acsmedchemlett.0c00392

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report here a fragment screen directed toward the c-MET kinase from which we discovered a series of inhibitors able to bind to a rare conformation of the protein in which the Ploop adopts a collapsed, or folded, arrangement. Preliminary SAR exploration led to an inhibitor (7) with nanomolar biochemical activity against c-MET and promising cell activity and kinase selectivity. These findings increase our structural understanding of the folded P-loop conformation of c-MET and provide a sound structural and chemical basis for further investigation of this underexplored yet potentially therapeutically exploitable conformational state.

引用

页码：162 / 167

页数：6

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