2X6E

Aurora-A bound to an inhibitor

Summary for 2X6E

• Entry DOI: 10.2210/pdb2x6e/pdb
• Related: 1MQ4 1MUO 1OL5 1OL6 1OL7 2BMC 2C6D 2C6E 2J4Z 2J50 2W1C 2W1D 2W1E 2W1F 2W1G 2WQE 2WTV 2WTW 2X6D
• Descriptor: SERINE/THREONINE-PROTEIN KINASE 6, 6-BROMO-7-{4-[(5-METHYLISOXAZOL-3-YL)METHYL]PIPERAZIN-1-YL}-2-[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]-1H-IMIDAZO[4,5-B]PYRIDINE (2 entities in total)
• Functional Keywords: transferase, mitosis, cell cycle
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965
• Total number of polymer chains: 1
• Total formula weight: 33500.26

Authors

Kosmopoulou, M.,Bayliss, R. (deposition date: 2010-02-17, release date: 2010-07-07, Last modification date: 2023-12-20)

Primary citation

Bavetsias, V.,Large, J.M.,Sun, C.,Bouloc, N.,Kosmopoulou, M.,Matteucci, M.,Wilsher, N.E.,Martins, V.,Reynisson, J.,Atrash, B.,Faisal, A.,Urban, F.,Valenti, M.,de Haven Brandon, A.,Box, G.,Raynaud, F.I.,Workman, P.,Eccles, S.A.,Bayliss, R.,Blagg, J.,Linardopoulos, S.,McDonald, E.
Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.
J. Med. Chem., 53:5213-5228, 2010

PubMed Abstract: Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.

PubMed: 20565112
DOI: 10.1021/jm100262j

Experimental method

X-RAY DIFFRACTION (3.35 Å)