4B0G

Complex of Aurora-A bound to an Imidazopyridine-based inhibitor

Summary for 4B0G

• Entry DOI: 10.2210/pdb4b0g/pdb
• Related: 1MQ4 1MUO 1OL5 1OL6 1OL7 2BMC 2C6D 2C6E 2J4Z 2J50 2W1C 2W1D 2W1E 2W1F 2W1G 2WQE 2WTV 2WTW 2X6D 2X6E 2X81 2XNE 2XNG 2XRU
• Descriptor: AURORA KINASE A, 6-bromo-2-(1-methyl-1H-imidazol-5-yl)-7-{4-[(5-methyl-1,2-oxazol-3-yl)methyl]piperazin-1-yl}-1H-imidazo[4,5-b]pyridine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transferase, mitosis
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965
• Total number of polymer chains: 1
• Total formula weight: 33662.24

Authors

Kosmopoulou, M.,Bayliss, R. (deposition date: 2012-07-02, release date: 2013-03-13, Last modification date: 2023-12-20)

Primary citation

Bavetsias, V.,Crumpler, S.,Sun, C.,Avery, S.,Atrash, B.,Faisal, A.,Moore, A.S.,Kosmopoulou, M.,Brown, N.,Sheldrake, P.W.,Bush, K.,Henley, A.,Box, G.,Valenti, M.,De Haven Brandon, A.,Raynaud, F.I.,Workman, P.,Eccles, S.A.,Bayliss, R.,Linardopoulos, S.,Blagg, J.
Optimization of Imidazo[4,5-B]Pyridine-Based Kinase Inhibitors: Identification of a Dual Flt3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid Leukemia.
J.Med.Chem., 55:8721-, 2012

PubMed Abstract: Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.

PubMed: 23043539
DOI: 10.1021/JM300952S

Experimental method

X-RAY DIFFRACTION (2.5 Å)