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.
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.
Collections
Subject
Aminopyridines
Peptide Fragments
Peptide Library
Protein Kinase Inhibitors
Drug Delivery Systems
Crystallography, X-Ray
Inhibitory Concentration 50
Molecular Structure
Research team
Medicinal Chemistry 1
Medicinal Chemistry 3
Hit Discovery & Structural Design
Language
eng
Date accepted
2018-04-15
License start date
2018-07
Citation
Bioorganic & medicinal chemistry, 2018, 26 (11), pp. 3021 - 3029
Publisher
PERGAMON-ELSEVIER SCIENCE LTD