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7-(Pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-based derivatives for kinase inhibition: Co-crystallisation studies with Aurora-A reveal distinct differences in the orientation of the pyrazole N1-substituent

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posted on 2016-02-10, 15:04 authored by V. Bavetsias, Y. Pérez-Fuertes, Patrick J. McIntyre, B. Atrash, M. Kosmopoulou, L. O’Fee, R. Burke, C. Sun, A. Faisal, K. Bush, S. Avery, A. Henley, F. I. Raynaud, S. Linardopoulos, R. Bayliss, J. Blagg
Introduction of a 1-benzyl-1H-pyrazol-4-yl moiety at C7 of the imidazo[4,5-b]pyridine scaffold provided 7a which inhibited a range of kinases including Aurora-A. Modification of the benzyl group in 7a, and subsequent co-crystallisation of the resulting analogues with Aurora-A indicated distinct differences in binding mode dependent upon the pyrazole N-substituent. Compounds 7a and 14d interact with the P-loop whereas 14a and 14b engage with Thr217 in the post-hinge region. These crystallographic insights provide options for the design of compounds interacting with the DFG motif or with Thr217.

Funding

This work was supported by CRUK Grant numbers C309/A8274 and C309/A11566. S.L. is also supported by Breakthrough Breast Cancer. R.B. acknowledges the support of a Royal Society Research Fellowship, Breakthrough Breast Cancer Project Grant AURA 05/06 and MRC CASE studentship MR/K016903/1. We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. Open Access funded by Cancer Research UK

History

Citation

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4203–4209

Version

  • VoR (Version of Record)

Published in

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4203–4209

Publisher

Elsevier for Pergamon

issn

0960-894X

eissn

1464-3405

Acceptance date

2015-08-03

Copyright date

2015

Available date

2016-02-10

Publisher version

http://www.sciencedirect.com/science/article/pii/S0960894X15008276

Notes

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.08. 003.

Language

en

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