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