5E1S

The Crystal structure of INSR Tyrosine Kinase in complex with the Inhibitor BI 885578

5E1S の概要

• エントリーDOI: 10.2210/pdb5e1s/pdb
• 分子名称: Insulin receptor, (5R)-N-(1-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-1H-pyrazol-3-yl)-5,8-dimethyl-9-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinazolin-2-amine (3 entities in total)
• 機能のキーワード: kinase, insr, igf-1r, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P06213
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35479.61

構造登録者

Kessler, D.,Zahn, S.,Sanderson, M.,Wolkerstorfer, B. (登録日: 2015-09-30, 公開日: 2015-10-14, 最終更新日: 2024-01-10)

主引用文献

Sanderson, M.P.,Apgar, J.,Garin-Chesa, P.,Hofmann, M.H.,Kessler, D.,Quant, J.,Savchenko, A.,Schaaf, O.,Treu, M.,Tye, H.,Zahn, S.K.,Zoephel, A.,Haaksma, E.,Adolf, G.R.,Kraut, N.
BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis.
Mol.Cancer Ther., 14:2762-2772, 2015

PubMed Abstract: Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP-competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance. BI 885578, administered daily per os, displayed an acceptable tolerability profile in mice at doses that significantly reduced the growth of xenografted human GEO and CL-14 colon carcinoma tumors. We found that treatment with BI 885578 is accompanied by increases in circulating glucose and insulin levels, which in turn leads to compensatory hyperphosphorylation of muscle INSRs and subsequent normalization of blood glucose within a few hours. In contrast, the normalization of IGF1R and INSR phosphorylation in GEO tumors occurs at a much slower rate. In accordance with this, BI 885578 led to a prolonged inhibition of cell proliferation and induction of apoptosis in GEO tumors. We propose that the remarkable therapeutic window observed for BI 885578 is achieved by virtue of the distinctive pharmacokinetic properties of the compound, capitalizing on the physiologic mechanisms of glucose homeostasis and differential levels of IGF1R and INSR expression in tumors and normal tissues.

PubMed: 26438154
DOI: 10.1158/1535-7163.MCT-15-0539

実験手法

X-RAY DIFFRACTION (2.264 Å)