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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

DOI: 10.1016/j.bmcl.2015.08.003 DOI Help
PMID: 26296477 PMID Help

Authors: Vassilios Bavetsias (Cancer Research UK) , Yolanda Pérez-fuertes (Cancer Research UK) , Patrick J. Mcintyre (University of Leicester) , Butrus Atrash (Cancer Research UK) , Magda Kosmopoulou (The Institute of Cancer Research) , Lisa O’fee (Cancer Research UK) , Rosemary Burke (Cancer Research UK) , Chongbo Sun (Cancer Research UK) , Amir Faisal (Cancer Research UK) , Katherine Bush (Cancer Research UK) , Sian Avery (Cancer Research UK) , Alan Henley (Cancer Research UK) , Florence I. Raynaud (Cancer Research UK) , Spiros Linardopoulos (Cancer Research UK) , Richard Bayliss (Institute of Cancer Research) , Julian Blagg (Cancer Research UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 25 (19) , PAGES 4203 - 4209

State: Published (Approved)
Published: October 2015
Diamond Proposal Number(s): 10369

Open Access Open Access

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.

Journal Keywords: Aurora-A; Imidazo[4,5-B]Pyridine; Aurora Kinase

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography