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.
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ICR Authors
Authors
Fearon, D
Westwood, IM
van Montfort, RLM
Bayliss, R
Jones, K
Bavetsias, V
Westwood, IM
van Montfort, RLM
Bayliss, R
Jones, K
Bavetsias, V
Document Type
Journal Article
Date
2018-07-15
Date Accepted
2018-04-15
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.
Citation
Bioorganic & medicinal chemistry, 2018, 26 (11), pp. 3021 - 3029
Source Title
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
ISSN
0968-0896
eISSN
1464-3391
Collections
Research Team
Medicinal Chemistry 1
Medicinal Chemistry 3
Hit Discovery & Structural Design
Medicinal Chemistry 3
Hit Discovery & Structural Design