Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

doi:10.1016/j.bmcl.2010.05.096

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 14, 15 July 2010, Pages 4045-4049

https://doi.org/10.1016/j.bmcl.2010.05.096 Get rights and content

Abstract

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.

Graphical abstract

Section snippets

Acknowledgements

We thank Dr. A. Mirza, M. Richards and Dr. M. Liu for assistance in the spectroscopic characterisation of test compounds and Dr M. Lamers for the preparation of CHK1 protein. This work was supported by Cancer Research UK [CUK] Grant Numbers C309/A2187, C309/A8274 and C309/A8365 and by The Institute of Cancer Research. We acknowledge NHS funding to the NIHR Biomedical Research Centre.

References and notes (24)

N. Foloppe et al.
Bioorg. Med. Chem.
(2006)
A.L. Hopkins et al.
Drug Discovery Today
(2004)
Z.A. Knight et al.
Chem. Biol.
(2005)
P. Cohen
Nat. Rev. Drug Disc.
(2002)
W.R. Pitt et al.
J. Med. Chem.
(2009)
A. Blasina et al.
Mol. Cancer Ther.
(2008)
S. Ashwell et al.
Clin. Cancer Res.
(2008)
N. Bucher et al.
Br. J. Cancer
(2008)
J.W. Janetka et al.
Curr. Opin. Drug Discov. Devel.
(2007)
T.P. Matthews et al.
J. Med. Chem.
(2009)

Ledeboer, M.; Davies, R. J.; Messersmith, D.; Moon, Y.-C.; Mullican, M. D. Patent Appl. WO2004058749, 2004; Chem....

Moon, Y. C.; Green, J.; Davies, R.; Choquette, D.; Pierce, A.; Ledeboer, M. Patent Appl. WO2002102800, 2002; Chem....

Cited by (27)

2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion
2014, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Swern oxidation22 to the ketones 19a–e was followed by acid-induced cyclisation to form the 3-aryl-8-chloroimidazo[1,2-a]pyrazines 20a–e. 3-substituted imidazo[1,2-a]pyrazine derivatives have previously been reported as kinase inhibitors,23–25 and a range of strategies is available for synthesis of the key heterocyclic core. However, 2-aryl imidazo[1,2-a]pyrazine derivatives have been less frequently explored,26 and consequently fewer synthetic approaches to these compounds have been reported.
A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents.
Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases
2013, Bioorganic and Medicinal Chemistry
Citation Excerpt :
The use of PKA as a surrogate of other AGC family kinases is well established.24,45 The binding mode for 12 (PDB 3Z01; Fig. 3A) showed the purine hydrogen bonding to the hinge peptide as expected, and the nitrogen of the azaspirocycle interacting with the side chain carboxylate of Glu127, a residue located in the ribose pocket and postulated to be involved in communicating ATP-binding to substrate–peptide binding residues.46 Compounds 14 and 16 (PDB 3Z02, 3ZO3; Fig. 3B, C) bound similarly to the hinge region but displayed an alternative interaction in the ribose pocket, with the azaspirocycle nitrogen interacting with the side chain carboxylate of Asp184 from the DFG motif, and close to Asn171 and the backbone carbonyl of Glu170.
With the success of protein kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery.
Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates
2012, Bioorganic and Medicinal Chemistry Letters
Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.
Six-membered ring systems. diazines and benzo derivatives
2011, Progress in Heterocyclic Chemistry
Citation Excerpt :
Many derivatives were synthesized and evaluated as potential cancer treatments. Compounds were found to be potent inhibitors of P38α MAP kinase (124) 〈10JMC1128〉, the Wnt2/β-catenin pathway in non-small-cell lung cancer cell lines 〈10BMCL5900〉, the folate cycle 〈10BMC7773〉, Pim kinase 〈10EJM5520〉, Aurora kinase (126) 〈10BMCL6739, 10BMCL5170, 10BMCL5988〉, CHK1 〈10BMCL4045〉, and Nek2 (127) 〈10JMC7682〉. The diaminopteridine-benzenesulfonamide 128 was evaluated as an inhibitor of carbonic anhydrases and dihydrofolate reductase 〈10BMC5081〉, while the phenazine 130 was evaluated as an inhibitor of quinone reductases 1 and 2, and inducible nitric oxide synthase 〈10JMC8688〉.
Structure-based design of imidazo[1,2-a]pyrazine derivatives as selective inhibitors of Aurora-A kinase in cells
2010, Bioorganic and Medicinal Chemistry Letters
Co-crystallisation of the imidazo[1,2-a]pyrazine derivative 15 (3-chloro-N-(4-morpholinophenyl)-6-(pyridin-3-yl)imidazo[1,2-a]pyrazin-8-amine) with Aurora-A provided an insight into the interactions of this class of compound with Aurora kinases. This led to the design and synthesis of potent Aurora-A inhibitors demonstrating up to 70-fold selectivity in cell-based Aurora kinase pharmacodynamic biomarker assays.
High-throughput virtual screening of novel CHK1 inhibitors
2023, Onkologia i Radioterapia

View all citing articles on Scopus

View full text

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

Abstract

Graphical abstract

Section snippets

Acknowledgements

Bioorg. Med. Chem.

Drug Discovery Today

Chem. Biol.

Nat. Rev. Drug Disc.

J. Med. Chem.

Mol. Cancer Ther.

Clin. Cancer Res.

Br. J. Cancer

Curr. Opin. Drug Discov. Devel.

J. Med. Chem.