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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.

ABSTRACT: 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.

SUBMITTER: Bavetsias V 

PROVIDER: S-EPMC4577729 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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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.

Bavetsias Vassilios V   Pérez-Fuertes Yolanda Y   McIntyre Patrick J PJ   Atrash Butrus B   Kosmopoulou Magda M   O'Fee Lisa L   Burke Rosemary R   Sun Chongbo C   Faisal Amir A   Bush Katherine K   Avery Sian S   Henley Alan A   Raynaud Florence I FI   Linardopoulos Spiros S   Bayliss Richard R   Blagg Julian J  

Bioorganic & medicinal chemistry letters 20150806 19

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  ...[more]

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