5IU2

Discovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors

5IU2 の概要

• エントリーDOI: 10.2210/pdb5iu2/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase 8, N-[2-(morpholin-4-yl)ethyl]-6-(8-phenyl-1H-imidazo[4,5-c][1,7]naphthyridin-1-yl)-1,3-benzothiazol-2-amine (3 entities in total)
• 機能のキーワード: cot, tpl-2, map3k8, kinase, inhibitor, complex, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P41279
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76285.62

構造登録者

Gutmann, S.,Hinniger, A. (登録日: 2016-03-17, 公開日: 2016-08-24, 最終更新日: 2025-01-29)

主引用文献

Glatthar, R.,Stojanovic, A.,Troxler, T.,Mattes, H.,Mobitz, H.,Beerli, R.,Blanz, J.,Gassmann, E.,Druckes, P.,Fendrich, G.,Gutmann, S.,Martiny-Baron, G.,Spence, F.,Hornfeld, J.,Peel, J.E.,Sparrer, H.
Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.
J.Med.Chem., 59:7544-7560, 2016

PubMed Abstract: Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.

PubMed: 27502541
DOI: 10.1021/acs.jmedchem.6b00598

実験手法

X-RAY DIFFRACTION (2.7 Å)