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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.
journal contribution
posted on 2017-01-20, 15:25 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, Richard Bayliss, J. BlaggIntroduction 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. We also thank Dr Amin Mirza, Mr Meirion Richards, Dr Maggie Liu for their assistance with NMR, mass spectrometry and HPLC, and Dr Charlotte Dodson for Aurora-A protein production. We thank Diamond Light Source for beamtime and the staff of beamlines I03 and I04 for assistance with data collection.
History
Citation
Bioorganic & Medicinal Chemistry Letters 25 (2015) 4203–4209Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell BiologyVersion
- VoR (Version of Record)
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Bioorganic & Medicinal Chemistry Letters 25 (2015) 4203–4209Publisher
Elsevierissn
0960-894Xeissn
1464-3405Acceptance date
2015-08-03Copyright date
2015Available date
2017-01-20Publisher DOI
Publisher version
http://www.sciencedirect.com/science/article/pii/S0960894X15008276Notes
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
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