5EW9

Crystal Structure of Aurora A Kinase Domain Bound to MK-5108

5EW9 の概要

• エントリーDOI: 10.2210/pdb5ew9/pdb
• 分子名称: Aurora kinase A, 4-(3-chloranyl-2-fluoranyl-phenoxy)-1-[[6-(1,3-thiazol-2-ylamino)pyridin-2-yl]methyl]cyclohexane-1-carboxylic acid (3 entities in total)
• 機能のキーワード: transferase, protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31998.99

構造登録者

Shiau, A.K.,Motamedi, A. (登録日: 2015-11-20, 公開日: 2016-01-20, 最終更新日: 2024-10-23)

主引用文献

de Groot, C.O.,Hsia, J.E.,Anzola, J.V.,Motamedi, A.,Yoon, M.,Wong, Y.L.,Jenkins, D.,Lee, H.J.,Martinez, M.B.,Davis, R.L.,Gahman, T.C.,Desai, A.,Shiau, A.K.
A Cell Biologist's Field Guide to Aurora Kinase Inhibitors.
Front Oncol, 5:285-285, 2015

PubMed Abstract: Aurora kinases are essential for cell division and are frequently misregulated in human cancers. Based on their potential as cancer therapeutics, a plethora of small molecule Aurora kinase inhibitors have been developed, with a subset having been adopted as tools in cell biology. Here, we fill a gap in the characterization of Aurora kinase inhibitors by using biochemical and cell-based assays to systematically profile a panel of 10 commercially available compounds with reported selectivity for Aurora A (MLN8054, MLN8237, MK-5108, MK-8745, Genentech Aurora Inhibitor 1), Aurora B (Hesperadin, ZM447439, AZD1152-HQPA, GSK1070916), or Aurora A/B (VX-680). We quantify the in vitro effect of each inhibitor on the activity of Aurora A alone, as well as Aurora A and Aurora B bound to fragments of their activators, TPX2 and INCENP, respectively. We also report kinome profiling results for a subset of these compounds to highlight potential off-target effects. In a cellular context, we demonstrate that immunofluorescence-based detection of LATS2 and histone H3 phospho-epitopes provides a facile and reliable means to assess potency and specificity of Aurora A versus Aurora B inhibition, and that G2 duration measured in a live imaging assay is a specific readout of Aurora A activity. Our analysis also highlights variation between HeLa, U2OS, and hTERT-RPE1 cells that impacts selective Aurora A inhibition. For Aurora B, all four tested compounds exhibit excellent selectivity and do not significantly inhibit Aurora A at effective doses. For Aurora A, MK-5108 and MK-8745 are significantly more selective than the commonly used inhibitors MLN8054 and MLN8237. A crystal structure of an Aurora A/MK-5108 complex that we determined suggests the chemical basis for this higher specificity. Taken together, our quantitative biochemical and cell-based analyses indicate that AZD1152-HQPA and MK-8745 are the best current tools for selectively inhibiting Aurora B and Aurora A, respectively. However, MK-8745 is not nearly as ideal as AZD1152-HQPA in that it requires high concentrations to achieve full inhibition in a cellular context, indicating a need for more potent Aurora A-selective inhibitors. We conclude with a set of "good practice" guidelines for the use of Aurora inhibitors in cell biology experiments.

PubMed: 26732741
DOI: 10.3389/fonc.2015.00285

実験手法

X-RAY DIFFRACTION (2.181 Å)