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. 2018 Jul 15;26(11):3021-3029.
doi: 10.1016/j.bmc.2018.04.033. Epub 2018 Apr 17.

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

Daren Fearon  1 , Isaac M Westwood  1 , Rob L M van Montfort  1 , Richard Bayliss  2 , Keith Jones  3 , Vassilios Bavetsias  4
Affiliations

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

Daren Fearon et al. Bioorg Med Chem. .

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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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Properties of 3-aminopyridin-2-one fragment 1.
Fig. 2
Fig. 2
Synthesis and members of 3-aminopyridin-2-one based fragment library. i: Aryl/Heteroaryl boronic acid, Pd2(dba)3, XPhos, K3PO4, n-butanol, 120 °C. ii: TMS-Cl, NaI, acetonitrile. iii: Bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, dioxane, 80 °C. iv: Aryl/Heteroaryl halide, Pd(PPh3)4, Na2CO3, toluene, EtOH, H2O, 100 °C. v: TMS-Cl, NaI, acetonitrile. vi: H2SO4, 120 °C. vii: NaOH, Br2. For synthesis of compound 4, see Supplementary Data Fig. 1, and for the synthesis of compounds 7 and 8, see Supplementary Data Fig. 2.
Fig. 3
Fig. 3
Line chart plotting the% inhibition at 100 µM A: 1 (Blue); 2 (Black); 3 (Green); 15 (Grey); B: 5 (Blue); 6 (Black); 7 (Green); 8 (Grey).
Fig. 4
Fig. 4
X-ray crystal structure of 2 (carbon atoms in yellow) bound to MPS1 (3.00 Å) with Fo-Fc omit map of 2 contoured at 3σ, clipped to 2 Å around 2 and displayed as a green mesh (PDB Code: 4CV8).
Fig. 5
Fig. 5
Synthesis of benzamidopyridin-2-one library. For synthesis of compound 24, see Supplementary Data. Also, for synthesis of compound 21, see Supplementary Data.
Fig. 6
Fig. 6
Line chart plotting the% inhibition for compounds 16 (Blue); 17 (Green); 22: (Black); 24 (Grey).
Fig. 7
Fig. 7
X-ray crystal structure of 23 (carbon atoms in yellow) bound to MPS1 (2.50 Å) with Fo-Fc omit map contoured at 3σ, clipped to 2 Å around 23 and displayed as a green mesh (PDB Code: 4CVA).
Fig. 8
Fig. 8
X-ray crystal structure of 22 bound to MPS1 (PDB Code: 4CV9) (purple with I663 and M602 shown as sticks) overlaid with the X-ray crystal structure of Aurora A (green with A273 and L210 shown as sticks).
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