title: 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.
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom. Electronic address: vassilios.bavetsias@icr.ac.uk.
authors: Vassilios
authors: V
authors: Bavetsias
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Yolanda
authors: Y
authors: Pérez-Fuertes
authors: University of Leicester, Department of Biochemistry, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors: Patrick J
authors: PJ
authors: McIntyre
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Butrus
authors: B
authors: Atrash
authors: Division of Structural Biology, The Institute of Cancer Research, London, United Kingdom.
authors: Magda
authors: M
authors: Kosmopoulou
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Lisa
authors: L
authors: O'Fee
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Rosemary
authors: R
authors: Burke
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Chongbo
authors: C
authors: Sun
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Amir
authors: A
authors: Faisal
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Katherine
authors: K
authors: Bush
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Sian
authors: S
authors: Avery
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Alan
authors: A
authors: Henley
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom.
authors: Florence I
authors: FI
authors: Raynaud
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom; Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research, London, United Kingdom.
authors: Spiros
authors: S
authors: Linardopoulos
authors: University of Leicester, Department of Biochemistry, Lancaster Road, Leicester LE1 9HN, United Kingdom; Division of Structural Biology, The Institute of Cancer Research, London, United Kingdom. Electronic address: richard.bayliss@leicester.ac.uk.
authors: Richard
authors: R
authors: Bayliss
authors: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, United Kingdom. Electronic address: julian.blagg@icr.ac.uk.
authors: Julian
authors: J
authors: Blagg
mesh_terms: D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D064127:Aurora Kinases
keywords: Aurora kinase; Aurora-A; Imidazo[4,5-b]pyridine