2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2018 Jul 15;26(11):3021-3029. doi: 10.1016/j.bmc.2018.04.033.
Daren Fearon 1,  Isaac M Westwood 1,  Rob L M van Montfort 1,  Richard Bayliss 2,  Keith Jones 3,  Vassilios Bavetsias 4
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SM2 5NG, UK.
  • 2 Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, UK.
  • 3 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: Keith.Jones@icr.ac.uk.
  • 4 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: Vassilios.Bavetsias@icr.ac.uk.
PMID: 29764757 DOI: 10.1016/j.bmc.2018.04.033
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.

Keywords

3-Aminopyridin-2-one; Aurora kinase; Fragment compound library; MPS1 kinase.

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