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Structural basis for targeting the folded P-loop conformation of c-MET

DOI: 10.1021/acsmedchemlett.0c00392 DOI Help

Authors: Gavin W. Collie (AstraZeneca) , Iacovos N. Michaelides (AstraZeneca) , Kevin Embrey (AstraZeneca) , Christopher J. Stubbs (AstraZeneca) , Ulf Börjesson (AstraZeneca) , Ian L. Dale (AstraZeneca) , Arjan Snijder (AstraZeneca) , Louise Barlind (AstraZeneca) , Kun Song (AstraZeneca) , Puneet Khurana (AstraZeneca) , Christopher Phillips (AstraZeneca) , R. Ian Storer (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: December 2020

Open Access Open Access

Abstract: 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 P-loop 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.

Journal Keywords: c-MET; kinase; X-ray crystallography; P-loop; small molecule inhibitor

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: Swiss Light Source

Added On: 14/12/2020 09:40


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)