5K3Y

Crystal structure of AuroraB/INCENP in complex with BI 811283

5K3Y の概要

• エントリーDOI: 10.2210/pdb5k3y/pdb
• 分子名称: Aurora kinase B-A, Inner centromere protein A, N-methyl-N-(1-methylpiperidin-4-yl)-4-{[4-({(1R,2S)-2-[(propan-2-yl)carbamoyl]cyclopentyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzamide, ... (4 entities in total)
• 機能のキーワード: kinase, inhibitor, transferase
• 由来する生物種: Xenopus laevis (African clawed frog); 詳細
• 細胞内の位置: Nucleus: Q6DE08 O13024
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 81388.26

構造登録者

Bader, G.,Zahn, S.K.,Zoephel, A. (登録日: 2016-05-20, 公開日: 2016-08-17, 最終更新日: 2024-11-20)

主引用文献

Sini, P.,Gurtler, U.,Zahn, S.K.,Baumann, C.,Rudolph, D.,Baumgartinger, R.,Strauss, E.,Haslinger, C.,Tontsch-Grunt, U.,Waizenegger, I.C.,Solca, F.,Bader, G.,Zoephel, A.,Treu, M.,Reiser, U.,Garin-Chesa, P.,Boehmelt, G.,Kraut, N.,Quant, J.,Adolf, G.R.
Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.
Mol.Cancer Ther., 15:2388-2398, 2016

PubMed Abstract: Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388-98. ©2016 AACR.

PubMed: 27496137
DOI: 10.1158/1535-7163.MCT-16-0066

実験手法

X-RAY DIFFRACTION (1.6 Å)