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Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2( 1H )-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition

DOI: 10.1016/j.bmc.2018.04.033 DOI Help

Authors: Daren Fearon (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Isaac M. Westwood (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Rob L. M. Van Montfort (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Richard Bayliss (University of Leeds) , Keith Jones (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Vassilios Bavetsias (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: April 2018

Open Access Open Access

Abstract: Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity.

Journal Keywords: 3-aminopyridin-2-one; Fragment compound library; Aurora kinase; MPS1 kinase

Subject Areas: Biology and Bio-materials, Chemistry


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