4b0g

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

Structural highlights 4b0g is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , 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 Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. 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.,Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J J Med Chem. 2012 Oct 25;55(20):8721-34. doi: 10.1021/jm300952s. Epub 2012 Oct 8. PMID:23043539 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase

spinqualitylabelsall models 4b0g, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image